Strategic integration of immunotherapy with chemotherapy, radiotherapy, and targeted therapy in gastric cancer management: A systematic review

Abstract

BACKGROUND

Gastric cancer (GC) poses significant treatment challenges due to late-stage diagnosis and the limited efficacy of conventional therapies. Immunotherapy, particularly immune checkpoint inhibitors such as pembrolizumab and nivolumab targeting the programmed death-ligand 1 (PD-L1) pathway, has shown promising results. Pembrolizumab is effective in PD-L1-positive tumors, while nivolumab improves overall survival and progression-free survival. Emerging therapies, including cancer vaccines and chimeric antigen receptor T-cell therapy, especially in human epidermal growth factor receptor 2 (HER2)-positive GC, offer additional avenues for improving outcomes.

AIM

To comprehensively evaluate the current evidence on the strategic integration of immunotherapy with chemotherapy, radiotherapy, and targeted therapies in the management of GC.

METHODS

This systematic review was conducted by analyzing clinical studies and trials on the integration of immunotherapy with chemotherapy, radiotherapy, and targeted therapy in GC. Databases such as PubMed, MEDLINE, and clinical trial registries were searched for studies published till June 2025. The review focused on combination strategies, treatment sequencing, molecular mechanisms, and the clinical impact of integrated therapies.

RESULTS

Evidence suggests that combining immunotherapy with chemotherapy exploits synergistic mechanisms, including immunogenic cell death and modulation of the tumor microenvironment. Similarly, the integration of immunotherapy with radiotherapy leverages the abscopal effect, enhancing systemic anti-tumor responses. Clinical trials involving combinations of immunotherapy with targeted therapies such as HER2, vascular endothelial growth factor receptor, and epidermal growth factor receptor inhibitors demonstrate improved survival outcomes in advanced GC. However, the optimal sequencing, dosing, and patient selection remain areas of active investigation.

CONCLUSION

The findings underscore the potential of immunotherapy, either alone or in combination with chemotherapy, radiotherapy, and targeted therapy, to transform GC management. Optimizing combination strategies and identifying predictive biomarkers are essential for improving therapeutic efficacy and patient outcomes. Future research should focus on refining these approaches to enhance survival and quality of life for patients with GC.

Key Words: Gastric cancer; Immunotherapy; Chemotherapy; Radiotherapy; Targeted therapy; Management

Core Tip: Gastric cancer remains challenging to treat due to late diagnosis and limited response to standard therapies. Immunotherapy, especially programmed cell death protein 1/programmed death-ligand 1 inhibitors like pembrolizumab and nivolumab, has shown promising results in improving survival. This systematic review emphasizes the benefits of integrating immunotherapy with chemotherapy, radiotherapy, and targeted therapy to enhance antitumor efficacy through mechanisms such as immunogenic cell death and the abscopal effect. Future studies should focus on optimizing treatment sequencing, dosing, and biomarker-based patient selection to refine combination strategies and improve survival and quality of life in patients with gastric cancer.

INTRODUCTION

Gastric cancer (GC) poses a critical global health challenge, ranking as the fifth most common cancer and the third leading cause of cancer deaths. In 2022 alone, it resulted in over one million new cases and approximately 769000 deaths[1]. The high mortality rate is largely due to GC's aggressive behavior and frequent late diagnosis, compounded by its diverse forms. This stark reality underscores the urgent need for improved strategies to effectively manage and combat this devastating disease[2]. The standard treatment for GC combines surgery, chemotherapy, radiotherapy, and more recently, targeted therapies. Despite these efforts, the prognosis for advanced GC remains poor, with 5-year survival rates markedly declining for patients diagnosed at later stages[3]. This situation highlights an urgent need for innovative and effective treatment approaches to offer better outcomes and renewed hope for those battling this cancer. In light of this, the advent of immunotherapy has emerged as a promising new frontier in cancer treatment[4]. By harnessing the body's immune system to recognize and destroy cancer cells, immunotherapy offers a unique mechanism of action distinct from traditional therapies[5-7]. Given this backdrop, the rationale for exploring the strategic integration of immunotherapy with existing modalities in GC management becomes compelling. This review provides a comprehensive overview of how immunotherapy can be synergistically combined with chemotherapy, radiotherapy, and targeted therapy to devise more effective treatment regimens.

To address the evolving complexity of multimodal treatment strategies in GC, we adopted a systematic and structured approach to synthesize current clinical and translational evidence. In this review, we outline how key signaling pathways including phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR), RAS/RAF/mitogen-activated protein kinase (MAPK), p53, and claudin-18.2 (CLDN18.2)-associated mechanisms shape therapeutic response or resistance to combination regimens. By linking these molecular interactions to observed therapeutic synergy, we establish a mechanistic foundation that connects commonly used clinical combinations with their underlying signaling architecture. Given the increasing integration of immunotherapy with chemotherapy, radiotherapy, and targeted therapy, we systematically evaluated contemporary clinical and preclinical studies to clarify how these combined approaches influence treatment efficacy, patient outcomes, and resistance mechanisms. We further considered treatment sequencing, dosing optimization, and toxicity-management strategies that may enhance the clinical utility of multimodal regimens.

To ensure comprehensive coverage, a structured literature search was conducted across major databases, including PubMed, Scopus, and Web of Science, using predefined keywords and inclusion criteria centered on therapeutic outcomes, synergistic mechanisms, and safety profiles. Eligible studies were screened, quality-assessed, and categorized by treatment modality to identify emerging trends, mechanistic synergies, and ongoing challenges in combination therapy.

Together, this integrated synthesis provides an evidence-based framework that connects molecular mechanisms with clinical combination strategies and highlights key considerations for advancing multimodal therapeutic integration in GC.

MATERIALS AND METHODS

Search strategy and information sources

This systematic review was conducted in accordance with PRISMA 2020 guidelines to ensure methodological transparency and reproducibility. A comprehensive literature search was performed across four major electronic databases PubMed/MEDLINE, Scopus, Web of Science, EMBASE, and Google Scholar to identify relevant studies published till June 2025. To broaden coverage, additional sources were screened, including reference lists of eligible studies, previous systematic reviews, grey literature, conference abstracts, and clinical trial registries such as ClinicalTrials.gov.

The search strategy employed a structured combination of keywords, Boolean operators, and database-specific Medical Subject Heading (MeSH) terms. Key components included disease-related terms (“gastric cancer”, “stomach cancer”, “gastroesophageal cancer”, “Gastric Neoplasms[Mesh]”), treatment-related terms (“immunotherapy”, “immune checkpoint inhibitors”, “chemotherapy”, “radiotherapy”, “targeted therapy”, “combination therapy”), and molecular-pathway terms (“RAS”, “RAF”, “MEK”, “ERK”, “MAPK”, “PI3K”, “AKT”, “mTOR”, “EGFR”, “HER2”, “p53”, “angiogenesis”). The full PubMed search string was adapted for Web of Science and EMBASE according to each database’s indexing structure. Searches were restricted to human studies and English-language publications.

Eligibility criteria

Studies were eligible for inclusion if they: (1) Evaluated immunotherapy alone or in combination with chemotherapy, radiotherapy, or targeted therapies in gastric or gastroesophageal cancer; (2) Reported clinically relevant outcomes such as overall survival (OS), progression-free survival (PFS), objective response rate (ORR), toxicity patterns, mechanistic insights, or treatment sequencing; and (3) Were published within the defined search period.

Eligible study designs included randomized controlled trials, observational studies, prospective and retrospective cohorts, and relevant translational research. Exclusion criteria comprised non-original articles (editorials, letters, commentaries, and opinion pieces), case reports with fewer than 5 patients, non-human studies lacking mechanistic relevance, non-English publications, duplicate entries, and conference abstracts without extractable data. Reasons for full-text exclusions were documented in accordance with predefined criteria. We followed the Population, Intervention, Comparator, Outcome (PICO) criteria[8].

Study selection process

All records were imported into reference-management software for de-duplication before screening. Study selection was performed in two stages. First, two investigators independently reviewed titles and abstracts to assess potential relevance. Second, full-text articles for shortlisted studies were evaluated in detail against the eligibility criteria. Disagreements were resolved through discussion or consultation with a third reviewer when necessary. The overall selection process is depicted in the PRISMA flow diagram (Figure 1).

Figure 1  PRISMA flow chart for the study selection for systematic review.

Data extraction

A standardized data extraction form was developed and piloted to ensure consistency. Two reviewers independently extracted key information, including study characteristics (author, year, geographic region, and design), patient demographics, sample size, molecular subtype, treatment regimens, sequencing or timing of combination therapies, biomarker data [e.g., programmed death-ligand 1 (PD-L1) combined positive score (CPS), human epidermal growth factor receptor 2 (HER2), microsatellite instability (MSI) status], clinical outcomes (OS, PFS, ORR), toxicity profiles (including Common Terminology Criteria for Adverse Events; grades), mechanistic insights, and clinical trial identifiers. Any discrepancies were resolved by cross-verification and consensus.

Quality assessment and risk-of-bias evaluation

Risk of bias was independently assessed by two reviewers using validated tools tailored to each study type. Randomized controlled trials were evaluated using the Cochrane Risk of Bias 2.0 tool, observational and cohort studies were assessed with the Newcastle-Ottawa Scale, and translational or mechanistic studies were appraised using the Critical Appraisal Skills Programme checklist. Quality assessments informed the interpretation of study findings, with reduced weighting applied to studies demonstrating higher risk of bias.

Data synthesis approach

Due to substantial heterogeneity in study designs, treatment regimens, biomarker stratification, and outcome measures, a quantitative meta-analysis was not feasible. Instead, a structured narrative synthesis was conducted, organized around three major therapeutic integration domains: (1) Chemo-immunotherapy; (2) Radio-immunotherapy; and (3) Targeted therapy combined with immunotherapy.

Within each domain, evidence was synthesized based on mechanistic rationale, reported clinical outcomes, toxicity considerations, and treatment sequencing strategies. This approach enabled a comprehensive and coherent interpretation of multimodal interactions and emerging therapeutic trends.

RESULTS

Signaling pathways in GC

The etiology of GC remains ambiguous, characterized by a complex interaction between environmental and genomic components. Perturbation of multiple genes and signaling pathways offer an adaptable environment to support the molecular and biochemical process of gastric carcinogenesis. Impairment in various signaling pathways linked with GC results in uncontrolled cell proliferation, growth, migration, invasion, and resistance to apoptosis.

RAS/RAF/MEK/ERK (MAPK) pathway: The RAS/RAF/MEK/ERK (MAPK) pathway is a critical signal transduction pathway involved in transmitting signals from cell surface receptors to the DNA in the nucleus. This pathway regulates cell proliferation, differentiation, and survival. Mutations or overexpression of components in this pathway can lead to continuous activation, promoting tumor growth and progression[9,10]. For instance, mutations in the KRAS gene are found in approximately 10% of GC cases, leading to the activation of downstream signaling and enhanced cell proliferation[11]. Gonzalez-Hormazabal et al[12] investigated the relationship between polymorphisms in the RAS/RAF/MEK/ERK pathway and GC. Their findings indicate that RAF1 rs3729931, HRAS rs45604736, MAPK1 rs2283792, and MAPK1 rs9610417 are linked to an increased risk of developing GC. Furthermore, mutations in other components of the MAPK pathway, such as BRAF and MEK, although less common, have also been implicated in gastrointestinal cancer. For instance, patients with metastatic colorectal cancer (mCRC) harboring class 2 BRAF mutations rarely respond to epidermal growth factor receptor (EGFR) antibody treatment. However, a substantial number of mCRC cases with class 3 BRAF mutations exhibit a favorable response. Thus, it is advisable to consider anti-EGFR antibody therapy for patients with class 3 BRAF-mutated colorectal cancer[13].

PI3K/AKT/mTOR pathway: The PI3K/AKT/mTOR signaling pathway plays a pivotal role in cell growth, survival, and metabolism. Upon activation by receptor tyrosine kinases such as EGFRs and vascular endothelial growth factor receptors (VEGFRs), PI3K phosphorylates phosphatidylinositol (4,5)-bisphosphate to phosphatidylinositol (3,4,5)-trisphosphate. This leads to the activation of AKT through phosphoinositide-dependent kinase-1[14]. Activated AKT phosphorylates tuberous sclerosis 1 (TSC1) and TSC2, which regulate mTOR, a key controller of cell growth. Additionally, AKT inhibits pro-apoptotic proteins and upregulates survival signals such as nuclear factor kappa B and p53[15]. Aberrations in this pathway are frequently observed in GC, with mutations in PIK3CA (the gene encoding the p110α subunit of PI3K) present in approximately 4% of cases[16]. Cho et al[17] documented that activation of GSK-3beta is frequently observed in early-stage gastric carcinoma and is associated with improved prognosis. Baicalein reduces hypoxia-induced AKT phosphorylation by increasing phosphatase and tensin homolog levels, which subsequently decreases hypoxia-inducible factor 1 alpha expression in GC cells. These results suggest inhibition of glycolysis could be key mechanisms in reversing 5-fluorouracil (5-FU) resistance in cancer cells under hypoxic conditions[18].

EGFR/HER2 pathway: The EGFR/HER2 pathway involves the activation of EGFR and HER2 receptors, which are commonly overexpressed in GC[19]. Activation of these receptors stimulates downstream signaling through the MAPK and PI3K/AKT pathways, leading to increased cell proliferation and survival. HER2 overexpression is observed in approximately 15%-20% of GC cases, and targeted therapies against EGFR and HER2, such as trastuzumab, have shown efficacy in treating GC[20]. Research indicates that high HER3 expression is associated with reduced patient survival, while HER2 overexpression is linked to poor prognosis in GC[21]. Notably, patients with HER2-positive GC often exhibit increased responsiveness to chemotherapy combined with HER2-targeted therapies[22]. Recent research has highlighted additional complexities in these pathways. For instance, HER2 mutations and amplifications can lead to resistance against standard therapies, prompting the need for novel therapeutic approaches[23]. Furthermore, the interplay between HER2 and other HER family members, such as HER3 and HER4, are gaining attention for its role in therapeutic resistance and disease progression[24]. Ongoing studies continue to investigate the potential of dual-targeting strategies and combination therapies to overcome resistance and improve clinical outcomes in patients with GC[25].

p53 pathway: The tumor suppressor p53 plays a crucial role in regulating the cell cycle and inducing apoptosis in response to DNA damage. Mutations in the p53 gene, which are frequent in GC, result in the loss of its tumor-suppressive functions, contributing to uncontrolled cell growth and survival[26]. The p53 tumor suppressor gene is frequently mutated in human cancers, including GC. These mutations can occur early in GC and become more common as the disease advances through defective cell cycle regulation and evasion of apoptosis[27]. The role of p53 in GC is further complicated by interactions with other pathways, such as PI3K/AKT and Wnt/β-catenin, which can also influence p53 activity and stability[28]. Additionally, mutant p53 proteins can acquire oncogenic properties that contribute to tumorigenesis, a phenomenon known as "gain of function"[29]. TP53-inducible nuclear protein 1 (TP53INP1) plays a crucial role in p53-mediated apoptosis and cell cycle arrest. In GC, the upregulation of microRNA 17-5p (miR-17-5p) and miR-20a can promote cell proliferation by downregulating TP53INP1 and p21[30]. Conversely, miR-499 can enhance the expression of p53 and its downstream target p21, thereby activating apoptotic pathways through caspase activation. Consequently, the downregulation of miR-449 observed in GC cells provides a survival advantage to the cancer cells[31]. Research indicates that over 75% of patients with GC exhibit elevated p53 expression. Additionally, the TP53 gene mutation rate in patients with GC is about 30%, though this rate can vary depending on the subtype and cause of the cancer[32]. Therefore, modulating TP53 expression is crucial for regulating the progression of GC.

Cell adhesion pathways (CLDN18): The CLDN18 gene encodes CLDN18, a crucial protein in tight junctions in epithelial cells that binds adjacent cells to create a barrier between external and internal environments and play role in maintaining cell-cell adhesion and epithelial integrity[33]. CLDN18 has two isoforms, CLDN18.1 and CLDN18.2, which differ in their first exon. Alterations in CLDN18 disrupt these functions, promoting cancer cell invasion and metastasis[34]. CLDN18.2 is predominantly expressed by differentiated cells of the gastric mucosa rather than stem cells. Its expression is maintained in a significant portion of GC[35]. Additionally, Xu et al[36] reported high CLDN18.2 expression rates in patients with advanced gastric signet-ring cell carcinoma. CLDN18-ARHGAP26 fusions are observed in a subset of GC cases, leading to dysregulation of cell adhesion and cytoskeletal dynamics[37]. Targeting CLDN18 has emerged as a potential therapeutic strategy, with ongoing research exploring monoclonal antibodies and other agents that can modulate CLDN18 activity. The expression of CLDN18 has been proposed as a biomarker for selecting patients who may benefit from CLDN18-targeted therapies[38]. The loss of cell polarity in GC reveals the CLDN8.2 epitope on tumor cell surfaces, making it an ideal therapeutic target due to its strong specificity and low toxicity.

Immune checkpoint pathways (programmed cell death protein 1/PD-L1 and cytotoxic T-lymphocyte-associated protein 4): Immune checkpoint (IC) pathways, including programmed cell death protein 1 (PD-1)/PD-L1 and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), play a crucial role in immune evasion by cancer cells. PD-1 is an inhibitory receptor expressed on T cells, while PD-L1 is its ligand expressed on tumor cells[39]. The interaction between PD-1 and PD-L1 inhibits T-cell activity, allowing cancer cells to evade immune detection. Transcriptome analysis of The Cancer Genome Atlas (TCGA) subtypes in GC has revealed significant upregulation of immune cell signaling in the Epstein-Barr virus-positive (EBV+) and MSI subtypes compared to the other two subtypes. The varying levels of immunomodulation among the four TCGA subtypes have led to a stratification strategy for patients with GC to enhance immunotherapy effectiveness. Immune cell signaling has become a focal point in GC research. EBV+ GC cases often exhibit a high content of immune cells; downregulation of genes involved in cytokine and chemokine pathways, and increased expression of PD-L1 and/or PD-L2[40]. It was observed that PD-L1 is expressed in 59.3% of patients with GC and is correlated with MSI and EBV+ subtypes. Gastric tumors positive for Helicobacter pylori (H. pylori) infection also exhibit higher PD-L1 expression and T-cell hyporesponsiveness, which is considered a mechanism of carcinogenesis due to H. pylori[41]. During the initiation and progression of GC, chronic infections with EBV or H. pylori induce a shift from a pro-inflammatory state, characterized by immune cell infiltration, to an immunosuppressive microenvironment where PD-L1 is upregulated in GC cells[42]. Inhibitors of these pathways, such as pembrolizumab and nivolumab, have been developed to enhance anti-tumor immunity in GC[43]. These IC inhibitors (ICIs) block the interaction between PD-1 on T cells and PD-L1 on tumor cells, thereby restoring T-cell activity against cancer cells. CTLA-4, another IC receptor, also contributes to immune suppression, and its blockade has shown promise in combination with PD-1/PD-L1 inhibitors[44]. Clinical trials have demonstrated the efficacy of these inhibitors in patients with advanced GC, particularly those with high microsatellite instability or elevated PD-L1 expression[5]. Understanding the molecular intricacies of these pathways is essential for developing more effective targeted therapies and improving patient outcomes in GC.

Immunotherapy and chemotherapy in GC

Recent advances in immunotherapy have provided new opportunities to improve survival outcomes in patients with GC. Immunotherapy enhances the immune system’s ability to recognize and eliminate malignant cells. Among the available strategies, ICIs targeting the PD-1/PD-L1 axis such as pembrolizumab and nivolumab have been particularly transformative. By blocking inhibitory immune interactions, these agents restore and amplify T-cell-mediated antitumor activity, thereby improving tumor recognition and immune clearance.

The development of ICIs that target the PD-1/PD-L1 pathway, such as pembrolizumab and nivolumab, has resulted in the most notable developments in this sector. Inhibiting abrupt functioning of the pathways leading to carcinogenesis improves the immune system's capacity to identify and eliminate cancer cells. According to Bang et al[45], clinical trials including patients with advanced GC have shown encouraging outcomes when using these ICIs. Based on the outcomes of the KEYNOTE-059 trial, the FDA approved pembrolizumab, an anti-PD-1 antibody, is potent for the treatment of patients with advanced GC that expresses PD-L1. The KEYNOTE-059 trials have looked at the effectiveness of pembrolizumab in treating patients with advanced stomach or gastroesophageal junction cancer. Patients who have undergone at least two rounds of therapy before having demonstrated an overall response rate (ORR) of 15.5% for pembrolizumab. Notably, the ORR raised to 22.7% in individuals whose tumors were PD-L1-positive. Furthermore, pembrolizumab demonstrated a tolerable safety profile, rendering it a feasible choice for patients who are not amenable to alternative therapies[5]. Pembrolizumab is also an effective treatment option for patients who are not eligible for other therapies because it has demonstrated a superior safety profile than traditional chemotherapy. Pembrolizumab plus chemotherapy was also assessed in the KEYNOTE-062 study as the initial treatment for individuals with advanced gastric or gastroesophageal junction cancer. According to the study, the combination did not significantly increase OS compared to chemotherapy alone. Nonetheless, the combination demonstrated a clinically significant improvement in OS in patients with high PD-L1 expression (CPS ≥ 10)[46].

An additional noteworthy advancement is the application of nivolumab, an anti-PD-1 antibody. The ATTRACTION-2 trial assessed the effectiveness of nivolumab in patients with advanced gastric or gastroesophageal junction cancer who had not responded to at least two previous chemotherapy regimens. It was a pivotal randomized, double-blind, placebo-controlled Phase 3 investigation. Compared to placebo, nivolumab dramatically increased OS, with a median OS of 5.26 months as opposed to 4.14 months. Nivolumab's effectiveness in this patient population was demonstrated by the 12-month OS rate of 26.6% for the nivolumab group and 10.9% for the placebo group, which represents a significant advancement in the treatment of GC[47]. The ATTRACTION-4 trial evaluated nivolumab as a first-line treatment for advanced GC when combined with chemotherapy (oxaliplatin and fluoropyrimidine). While the OS effect was not statistically significant, this Phase 3 study showed that combination therapy considerably increased PFS when compared to chemotherapy alone[48]. The CheckMate-649 trial compared chemotherapy alone and nivolumab plus chemotherapy for patients with advanced gastric, gastroesophageal junction, or esophageal adenocarcinomas that had not previously received treatment. According to Janjigian et al[49], the combination therapy significantly improved both OS and PFS (progression-free survival), especially in patients with PD-L1 expression (CPS ≥ 5).

Beyond ICIs, emerging immunotherapeutic approaches such as cancer vaccines and adoptive cell therapies are being actively explored. These include dendritic-cell vaccines and chimeric antigen receptor (CAR) T-cell therapies. Early-phase studies have shown encouraging results, particularly in HER2-positive disease. Long-lasting responses have been reported in advanced HER2-positive GC treated with HER2-targeted CAR-T cells, highlighting a promising future direction for GC immunotherapy[50].

Despite these advances, immunotherapy does not benefit all patients with GC, and both primary and acquired resistance remain major obstacles to durable treatment responses[51]. These limitations have intensified interest in combination approaches, particularly with chemotherapy, which provides complementary immunological effects that may enhance the performance of ICIs.

Chemotherapy continues to serve as the cornerstone of GC management, especially in advanced disease. Beyond its direct cytotoxic activity against rapidly proliferating tumor cells, chemotherapy exerts potent immunomodulatory effects that can synergize with ICIs. Notably, several chemotherapy agents induce immunogenic cell death (ICD), characterized by calreticulin exposure, extracellular ATP release, and high mobility group box 1 protein secretion. These hallmark signals promote dendritic cell (DC) maturation and strengthen antigen presentation to CD8+ cytotoxic T cells, thereby increasing tumor immunogenicity and improving responsiveness to IC blockade[52].

Chemotherapy also reduces immunosuppressive elements within the tumor microenvironment (TME), including regulatory T cells (Tregs), myeloid-derived suppressor cells (MDSCs), and tumor-associated macrophages (TAMs). The depletion of these populations diminishes immune evasion and supports more robust antitumor immune activity[53].

Furthermore, key signaling pathways frequently dysregulated in GC such as the RAS/RAF/MEK/ERK and PI3K/AKT/mTOR cascades critically influence tumor sensitivity to chemo-immunotherapy. Chemotherapy-induced DNA damage can upregulate tumor antigen presentation machinery and enhance major histocompatibility complex (MHC) expression, thereby improving tumor visibility to the immune system. Conversely, PD-1 blockade can counteract pathway-driven mechanisms of immune escape, strengthening T-cell mediated cytotoxicity[54].

Collectively, these mechanistic insights provide strong biological justification for integrating cytotoxic chemotherapy with immune-based therapies to overcome resistance and improve clinical outcomes in GC. Even yet, there are still a number of obstacles to overcome. Immunotherapy does not work for every patient, and the mechanisms underlying resistance are not entirely understood. Treatment for GC still primarily relies on chemotherapy, especially when the disease is advanced. It functions by directly destroying cancer cells that divide quickly, but it also has immunomodulatory properties that can improve the effectiveness of immunotherapy. Chemotherapy drugs can make tumors more immunogenic by causing ICD, which releases tumor antigens and encourages antigen presentation to T cells. Additionally, chemotherapy can deplete immunosuppressive cells within the TME, such as Tregs and MDSCs, thereby enhancing the anti-tumor immune response[52].

To address resistance and enhance clinical benefit, numerous ongoing clinical trials are evaluating combinations of immunotherapy with chemotherapy, targeted therapies, and novel immune-modulating agents. These studies are expected to refine treatment sequencing, identify predictive biomarkers, and improve patient stratification[55]. Immunotherapy therefore remains a promising and rapidly advancing therapeutic avenue for GC. Although ICIs such as pembrolizumab and nivolumab have demonstrated meaningful progress, continued development of next-generation immunotherapies, rational combination strategies, and robust precision biomarkers will be essential to further improve outcomes for patients with GC.

Immunotherapy and radiotherapy: A synergistic approach in GC treatment

Combining radiotherapy and immunotherapy, which has long been a mainstay in cancer treatment due to its benefits for local control, may have synergistic effects that could improve outcomes in GC[56]. Immunotherapy, in particular, ICIs, have emerged as a promising treatment modality, enhancing anti-tumor immune responses[57]. Combining radiation and immunotherapy has become a viable cancer treatment approach, utilizing the distinct properties of both modalities to boost anti-tumor responses. The present research delves into the mechanical reasoning, specifically examining the notion of the "abscopal effect," and examines the clinical data that bolster the joint application of these treatments, including the most effective sequencing, radiation dosages, and noted therapeutic outcomes by linking these effects to major oncogenic signaling pathways such as cyclic GMP-AMP synthase - stimulator of interferon (IFN) genes (cGAS-STING), RAS/RAF/MAPK, and PI3K/AKT/mTOR, which regulate DNA-damage responses, inflammatory signaling, and tumor immune evasion[58].

Mechanistic rationale - the abscopal effect: A phenomenon known as the "abscopal effect" occurs when localized radiation therapy not only causes tumor regression at the treated location but also immune-mediated responses that cause metastatic cancers at distant sites to retreat as a result. This outcome emphasizes how radiation therapy may function as an in situ vaccine, boosting immunity against tumors across the body. The main way that radiation therapy works on cancer cells is by damaging their DNA, which ultimately results in cell death. Tumor-associated antigens and danger-associated molecular patterns (DAMPs) are released into the surrounding tissue during this process. DCs can be stimulated by these antigens and signals, and DCs can then transmit the antigens to T cells, which starts a systemic immunological response[59], while simultaneously activating the cGAS-STING pathway, a central cytosolic DNA-sensing mechanism that enhances type I IFN production and improves antigen presentation, thereby amplifying the immunogenic effects of radiation[60].

When combined with immunotherapy, particularly ICIs such as anti-PD-1, anti-PD-L1, and anti-CTLA-4 antibodies, the potential for inducing the abscopal effect is enhanced. ICIs work by blocking inhibitory pathways that limit T-cell activation, thereby amplifying the immune response against cancer cells. By combining radiotherapy's ability to enhance antigen presentation with immunotherapy's capacity to boost T-cell activity, the likelihood of achieving systemic tumor control is increased[61]. Moreover, radiation-induced DAMPs can suppress PI3K/AKT- and MAPK-mediated immune-evasion signaling, thereby increasing tumor susceptibility to ICIs[62].

Numerous preclinical and clinical studies have evaluated the potential synergistic effects of combining immunotherapy with radiation. This manuscript discusses several key aspects of this approach, including optimal treatment sequencing, appropriate radiation dosing, and therapeutic outcomes. Emerging evidence further indicates that radiation-induced modulation of the TME can alter PD-L1 expression through activation of the RAS/RAF/MAPK pathway, thereby enhancing the synergy between radiotherapy and PD-1/PD-L1 blockade[63].

Optimal sequencing: To maximize synergistic efficacy, the timing of immunotherapy relative to radiotherapy requires careful optimization. Preclinical evidence suggests that concurrent administration of ICIs and radiation enhances CTL infiltration and activation. In a 2014 melanoma mouse model, Dovedi et al[64] demonstrated that simultaneous anti-PD-1 therapy and radiotherapy significantly improved survival compared with sequential scheduling. Clinical studies have also explored different sequencing strategies. The PEMBRO-RT Phase 1/2 trial in patients with non-small cell lung cancer (NSCLC) evaluated pembrolizumab given alongside radiotherapy. As reported by Theelen et al[65], concurrent treatment produced a higher ORR than pembrolizumab alone, supporting the superiority of contemporaneous administration. Mechanistically, concurrent ICI radiation therapy allows optimal synchronization of cGAS-STING activation with checkpoint-release signaling and may prevent rebound activation of the PI3K/AKT survival pathway that can occur with delayed or sequential dosing[66].

Radiation doses: Radiation dose and fractionation play a critical role in shaping the immune response. Hypofractionated radiotherapy delivering higher doses per fraction over fewer sessions has been shown to more effectively induce abscopal effects than conventional fractionation. Larger per-fraction doses generate stronger inflammatory signaling and promote ICD. In a seminal 2009 study, Dewan et al[67] demonstrated that hypofractionated radiation combined with anti-CTLA-4 therapy markedly improved tumor control and survival in a mouse model compared with standard fractionation. Clinical evidence further supports the enhanced efficacy of higher-dose fractions in potentiating immunotherapy[68]. Mechanistically, increased per-fraction doses amplify DNA damage signaling, resulting in stronger cGAS-STING activation and more pronounced suppression of pro-survival PI3K/AKT and MAPK pathways. This collectively enhances tumor susceptibility to immune-mediated elimination[69].

Observed therapeutic effects: Clinical investigations provide strong evidence supporting the therapeutic synergy between immunotherapy and radiotherapy. In patients with stage III NSCLC, the PACIFIC trial demonstrated that durvalumab administered after chemoradiotherapy significantly improved both PFS and OS compared with chemoradiotherapy alone[70]. Similarly, the KEYNOTE-001 trial in advanced melanoma reported that patients with prior radiation exposure experienced markedly better PFS and OS with pembrolizumab than those without previous radiation treatment[71]. These findings suggest that radiation-induced modulation of PD-L1 expression and enhanced antigen release driven in part by RAS/RAF/MAPK signaling and activation of cytosolic DNA-sensing pathways primes the TME for a more robust response to PD-1 blockade[72].

Emerging combination strategies: Recent advances have accelerated the exploration of innovative strategies combining immunotherapy with radiotherapy. For instance, the integration of ICIs with stereotactic body radiation therapy (SBRT) is being actively investigated across multiple cancer types. Additional approaches are evaluating novel ICIs such as those targeting T-cell immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domain and lymphocyte activation gene-3 in combination with radiation. These emerging strategies aim to enhance antitumor immunity and overcome resistance mechanisms that limit the effectiveness of current immunotherapeutic modalities[73]. There is particular interest in how SBRT influences the cGAS-STING pathway and modulates PI3K/AKT-driven radiosensitivity, providing a strong mechanistic rationale for these evolving combination therapies[69].

Immunotherapy and targeted therapy in GC

Immunotherapy plus targeted therapy has drawn a lot of interest as a cutting-edge and successful way to treat a variety of malignancies, including GC. This study delves into the molecular reasoning for this combination, emphasizing the ways in which targeted medicines can improve immune-mediated assault by modifying the TME. Moreover, it provides a summary of clinical data from studies examining the effects of immunotherapy and targeted medicines like HER2 inhibitors on treatment efficacy and tolerability.

Mechanistic rationale - modulating the TME: In the case of GC, targeted therapies aim to block particular biochemical pathways that are vital to the growth and survival of the tumor. Additionally, by changing the TME, these treatments may increase a tumor's vulnerability to immune-mediated attack. The extracellular matrix, immune cells, stromal cells, and cancer cells make up the TME, which is essential for both tumor growth and immune evasion. Immuno-suppressive cells that impede efficient anti-tumor immunity, such as Tregs and MDSCs, are frequently seen in the TME. Targeted treatments have the ability to decrease these cells' quantity or suppressive capacity. To alleviate immune suppression and enhance immune response, VEGF inhibitors, for instance, can lower MDSC numbers and disrupt tumor angiogenesis[74]. A defining feature of the TME is abnormal tumor vasculature, which limits T-cell invasion and fosters a hypoxic environment that aids in immune evasion. T-cell infiltration and function can be facilitated by targeted therapy, especially those that target VEGF, which can normalize tumor blood vessels and improve oxygenation[75].

Enhanced antigen presentation and immune recognition: By increasing the appearance of tumor antigens, targeted medicines can help the immune system recognize cancer cells more easily. For instance, MHC molecules may be expressed more often on tumor cells as a result of HER2 inhibitors like trastuzumab. This improves how tumor antigens are presented to CTLs, which strengthen the immune response, against the tumor[31]. Immune pathways can be directly stimulated by some targeted medicines. For instance, pro-inflammatory cytokines can be produced as a result of inhibitors that target the EGFR pathway, which can improve T-cell activation and recruitment[76]. Lesterhuis et al[77] showed that combining these benefits with ICIs greatly increases anti-tumor immunity.

Clinical evidence - combining targeted therapies and immunotherapy: The use of immunotherapy in conjunction with targeted medicines has been studied in a number of clinical studies for GC.

HER2 inhibitors in HER2-positive GC: HER2 is a key receptor in cancer development. When HER2 interacts with other family members like HER1 and HER3, it activates important signaling pathways, including PI3K/AKT/mTOR and MAPK/ERK1/2, that promote tumor growth and survival. Targeting HER2 and these pathways is a powerful strategy for treating HER2-positive tumors, helping to overcome resistance and improve patient outcomes[15].

In GC the HER2-positive subtype is defined by high levels of HER2 protein. Targeted treatments like trastuzumab have significantly improved the effectiveness of chemotherapy and increased survival rates for these patients[16]. Margetuximab, a Fc-engineered, anti-HER2 monoclonal antibody, is also effectively increase the innate immunity than trastuzumab[72]. The goal of combining immunotherapy and HER2 inhibitors is to improve anti-tumor immunity and get past resistance mechanisms. In patients with HER2-positive advanced GC, the KEYNOTE-811 trial, a Phase 3 study has assessed the efficacy of pembrolizumab, an anti-PD-1 antibody, in conjunction with trastuzumab and chemotherapy[78]. Another study was the Phase 2 INTEGRATE trial, which assessed the efficacy of pembrolizumab plus lapatinib (a dual HER2 and EGFR inhibitor) in treating HER2-positive GC. With an ORR of 27% and a disease control rate of 57%, the combination demonstrated an acceptable safety profile and exhibited promise efficacy[79].

VEGF inhibitors in GC: Tumor angiogenesis is dependent on the VEGF pathway, which is the target of VEGF inhibitors like ramucirumab. These drugs have the potential to improve anti-tumor immunity by regulating tumor vasculature and lowering immune-suppressive cell populations when used with immunotherapy. The combination of ramucirumab, pembrolizumab, and chemotherapy was assessed in patients with advanced GC as part of the RAINFALL trial. Comparing the combination to chemotherapy alone, the trial found that the ORR and PFS were higher, and the safety profile was tolerable[5].

The REGONIVO trial examined the use of nivolumab, an anti-PD-1 antibody, in conjunction with regorafenib, a multi-kinase inhibitor that targets VEGF, in the treatment of GC and colorectal cancer. According to Fukuoka et al[80], the combination showed a significant ORR of 44% in patients with GC and tolerable tolerability, indicating a synergistic impact. Lenvatinib, a multikinase inhibitor of VEGF receptors and other receptor tyrosine kinases, considerably augment the anti-tumor activity through reducing the TAMs and increased infiltration of CD8+ T cells along with pembrolizumab in patients with advanced GC in the first-line or second-line setting[81].

EGFR inhibitors: Gastritis is frequently associated with EGFR mutations and overexpression; to improve the effectiveness of immunotherapy, EGFR inhibitors like cetuximab and panitumumab have been investigated in conjunction with it[82]. The use of cetuximab in conjunction with nivolumab in patients with advanced EGFR-positive GC was examined in a Phase 1b trial. According to the study, the illness control rate was 54%, the ORR was 23%, and the safety profile was tolerable[47].

Analogously, a Phase 2 trial assessed panitumumab in conjunction with pembrolizumab. The outcomes demonstrated a higher ORR and PFS, underscoring the possible advantages of combining ICIs with EGFR inhibitors for GC treatment[83].

Hepatocyte growth factor/c-mesenchymal-epithelial transition pathway inhibitors: The mesenchymal-epithelial transition (MET), a tyrosine kinase receptor belonging to the MET families, with hepatocyte growth factor (HGF) as ligand that on activation triggers various cellular signaling pathways including Ras/MAPK and PI3K/AKT that are involved in cell cycle progression, cell proliferation, motility, migration, angiogenesis, migration, and differentiation and invasion[84]. The abnormal activation of this pathway linked to tumor invasion and metastasis such as gastrointestinal tract cancers. Events like MET gene amplification, high c-MET expression, and co-expression of HGF and c-MET are associated with worse prognosis in GC. Thus HGF/c-MET are vital biomarkers and potential targets in GC. Rilotumumab is a fully human mAb that selectively targets the ligand of the MET receptor that is HGF. In the Phase 2 trial RILOMET-1 trial, rilotumumab demonstrated anti-tumor efficacy in gastric and gastroesophageal cancer, whereas, the Phase 3 RILOMET-1 trial, the rilotumumab with chemotherapy showed poor outcome[85]. Savolitinib, a selective c-MET tyrosine kinase inhibitor showed some positive response with advanced GC[86].

CLDN18.2-targeted therapy: CLDNs, transmembrane proteins involve in the tight junction formation between cells. Its expression is modulated by various signaling pathways such as ERK/MAPK, HER2/HER3[87] CLDN18 involve in tumor cell proliferation, differentiation, and migration, specifically, the stomach-specific isoform CLDN18.2. Its expression is downregulated as an early event in gastric carcinogenesis unlike normal gastric cells where it is highly expressed, thus is emerging as a potential target in GC[88]. Its expression is higher in diffuse-type GC compared to intestinal-type and is also directly correlated with HER2 positivity[89]. Agents such as zolbetuximab (claudiximab, IMAB362), a chimeric IgG1 monoclonal antibody against CLDN18.2 are promising immunotherapeutic agents that induces antibody-dependent and complement-dependent cytotoxicity[90]. Thus, CLDN18.2 has significant implications for the diagnosis, treatment, and management of GC.

IC-targeted therapies: ICIs can be highly effective in treating GC. These therapies work by blocking the pathways that cancer cells use to evade the immune system. The primary checkpoints targeted are PD-1/PD-L1 (PD-1 - an inhibitory receptor expressed on T cells/PD-L1 - expressed on cancer cells) and CTLA-4. The PD-1/PD-L1 pathways are critical mechanisms acts as inhibitory checkpoints by which cancer cells evade the immune system. PD-L1 binds to PD-1 on T cells that reduces the T-cell activity leading to decreased immune response against cancer cells and promoting their survival[74]. CTLA-4 binds to the B7-1/2 protein of antigen-presenting cells (APCs), an inhibitory signal arises that dampens T-cell activity, preventing an overactive immune response, and in the context of cancer, reducing the ability of T cells to attack tumor cells. Both of these pathways are upregulated in tumor cells during tumor progression, suppressing the body's ability to mount an effective anti-tumor immune response and allowing the tumor to evade immune attack. Thus, targeting these immune is vital approach in cancer immunotherapy, including in the management of GC[91]. The anti-PD-1/PD-L1 and anti-CTLA-4 antibodies are the therapeutic agents that block the inhibitory interactions in these pathways and restoring the ability of T cells to recognize and destroy cancer cells. One of the trail of KEYNOTE-059 studies showed effectiveness of pembrolizumab plus chemotherapy (cisplatin plus 5-FU or capecitabine) for antitumor activity. This combination leverages the benefits of chemotherapy in enhancing immune responses while simultaneously targeting ICs to prevent tumor evasion. The other immune inhibitor, nivolumab, which is a fully human monoclonal antibody that inhibits the interaction between PD-1 and PD-L1 have enhanced the OS when administered with chemotherapy. CTLA-4 is another key checkpoint receptor that regulates T-cell activity. CTLA-4 competes with CD28 for binding to B7-1 and B7-2 proteins on APCs. When CTLA-4 binds to these proteins, it delivers an inhibitory signal that dampens T-cell activation and proliferation, preventing an excessive immune response. In the context of cancer, this inhibition reduces the ability of T cells to attack tumor cells. Anti-CTLA-4 antibodies, such as ipilimumab, block this inhibitory interaction, thereby enhancing T-cell activation and promoting a stronger immune response against tumors[92]. Ipilimumab was initially developed for melanoma but has shown promise in combination with other therapies for various cancers, including GC. CheckMate-649, a global, randomized, Phase 3 trial have shown that ICIs like nivolumab plus ipilimumab, a CTLA-4 inhibitor are effective to treat GC[93]. The effectiveness of PD-1/PD-L1 and CTLA-4 inhibitors can be significantly improved when combined with other treatment strategies. Integrating ICIs with targeted therapies can lead to enhanced therapeutic outcomes. Targeted therapies can alter the TME by improving the presentation of antigens and decreasing factors that suppress the immune response. This modification of the TME can, in turn, amplify the effectiveness of ICIs[94].

Combination therapy mechanism: By combining the benefits of both targeted therapy and immunotherapy, a potent treatment strategy for GC is provided, maximizing anti-tumor responses. Targeted treatments have the ability to mechanistically alter the TME, increasing the susceptibility of tumors to immune-mediated assault through the improvement of antigen presentation, the depletion of immunosuppressive cells, the restoration of normal tumor vasculature, and the cooperative activation of immune pathways. Research and clinical trials will continue to optimize these combination tactics as our understanding of the interactions between immunotherapy and targeted medicines deepens, ultimately improving outcomes for patients with GC. Table 1 summarizes the different combinational targeted therapy in GC targeting different signaling pathways (Figure 2).

Figure 2 Overview of signaling pathways in gastric cancer: Targeted molecular therapy and immunotherapy integration. Alterations in signaling pathways leading to gastric cancer (GC) development and progression, such as RAS/RAF/mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK)/ERK1/2, phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) pathways, human epidermal growth factor receptor 2 (HER2), hepatocyte growth factor (HGF)/c-mesenchymal-epithelial transition (MET), p53, nuclear factor kappa B (NF-κB), claudin 18, programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) are depicted. Some of the representative therapeutic targets (targeted or immunotherapeutic) in GC are illustrated. PDK1: Phosphoinositide-dependent kinase 1; VEGFR: Vascular endothelial growth factor receptor. Created in https://BioRender.com (Supplementary material).

Table 1 Summary of all combinational targeted therapy in gastric cancer[3,90-93].

Treatment combination	Mechanistic rationale	Key clinical trials	Main findings	Outcomes
Targeted therapy in GC	Targeted therapies aim to interfere with specific molecules involved in tumor growth and progression, such as HER2, VEGF, and EGFR, offering a more precise approach to cancer treatment	ToGA (trastuzumab for HER2-positive) NCT01041404. RAINBOW (ramucirumab for VEGFR2-positive) NCT02898077. REAL-3 (panitumumab for EGFR-positive NCT00824785	ToGA showed significant improvement in OS for HER2-positive GC patients treated with trastuzumab plus chemotherapy. RAINBOW demonstrated an increase in OS with Ramucirumab plus chemotherapy in VEGFR2-positive patients. REAL-3 did not show a survival benefit with the addition of panitumumab to chemotherapy	Improved survival in targeted patient populations. Potential for more personalized cancer treatment
Radiotherapy + targeted therapy	Targeted therapy can sensitize cancer cells to radiation by inhibiting DNA repair mechanisms, enhancing cell cycle control, or altering tumor oxygenation, thereby increasing the efficacy of radiotherapy	RTOG 1010 (for HER2-positive GC) NCT01196390. ARTIST-II (for adjuvant setting) NCT01761461	RTOG 1010 evaluated the addition of trastuzumab to chemoradiation for HER2-positive esophago GC, showing trends toward improved outcomes. ARTIST-II investigated adjuvant chemoradiotherapy plus targeted therapy in locally advanced GC, showing improved disease-free survival in certain subgroups	Potential improvement in locoregional control and disease-free survival, especially in genetically selected patient populations
Immunotherapy + chemotherapy	The combination exploits chemotherapy's ability to increase tumor antigenicity and reduce immunosuppressive elements in the tumor microenvironment, thereby enhancing the effectiveness of immunotherapy	CheckMate-649 NCT02872116. KEYNOTE-062 NCT02494583	CheckMate-649 showed a significant improvement in OS and PFS with the combination of nivolumab and chemotherapy in patients with advanced GC. KEYNOTE-062 evaluated the efficacy of pembrolizumab plus chemotherapy, demonstrating a durable response in a subset of patients with PD-L1-positive tumors	Increased OS and PFS in selected patient populations. Enhanced response rates, particularly in PD-L1-positive patients

EGFR: Epidermal growth factor receptor; GC: Gastric cancer; HER2: Human epidermal growth factor receptor 2; OS: Overall survival; PD-L1: Programmed death-ligand 1; PFS: Progression-free survival; VEGF: Vascular endothelial growth factor; VEGFR: Vascular endothelial growth factor receptor.

Challenges and future directions

Managing treatment: GC treatment has evolved significantly, with combination therapies demonstrating improved outcomes compared to monotherapies[95]. However, these advancements come with increased toxicity, presenting substantial challenges in clinical management. Combination therapies in GC typically involve chemotherapeutic agents, targeted therapies, and immunotherapies. While these regimens can enhance therapeutic efficacy, they also result in a higher incidence of adverse effects[96]. These toxicities can range from mild to severe, impacting patient quality of life and adherence to treatment protocols[97]. Chemotherapy remains a key component in the management of GC, particularly for advanced stages of the disease. Commonly used chemotherapeutic agents include cisplatin, 5-FU, and taxanes such as paclitaxel. The concurrent use of these drugs increases the risk of overlapping toxicities. For instance, cisplatin is widely used for its efficacy in treating various cancers, including GC. However, it is associated with significant nephrotoxicity, which can manifest as acute kidney injury or electrolyte imbalances[98]. Gastrointestinal side effects such as nausea, vomiting, and diarrhea are also common. Additionally, cisplatin can cause myelosuppression, leading to increased susceptibility to infections, anemia, and bleeding[99]. 5-FU is another cornerstone of chemotherapy for GC. Its adverse effects include gastrointestinal symptoms like mucositis, diarrhea, and nausea[100]. Myelosuppression is also a notable side effect, potentially resulting in neutropenia, anemia, and thrombocytopenia. Moreover, hand-foot syndrome, characterized by redness, swelling, and pain in the palms and soles, can occur[101]. Paclitaxel, a taxane, is utilized for its anti-cancer properties but can cause peripheral neuropathy, resulting in numbness, tingling, or pain in the extremities[102]. It also contributes to myelosuppression and can cause hypersensitivity reactions and gastrointestinal disturbances[103]. Targeted therapies, including agents like trastuzumab, have become integral in treating specific subtypes of GC, particularly HER2-positive tumors. The risk of cardiotoxicity is heightened when trastuzumab is used in combination with other cardiotoxic agents such as anthracyclines, and these cumulative adverse effects can be challenging to manage[104,105]. The integration of immunotherapies, such as CIs, has introduced new toxicity profiles[106]. Ramucirumab, an anti-VEGFR2 agent, is used for its anti-angiogenic properties but can cause hypertension, proteinuria, and an increased risk of bleeding. It may also lead to gastrointestinal perforations and complications with wound healing[107]. Recently, immune-related adverse events can affect various organ systems, including the skin, liver, gastrointestinal tract, and endocrine glands[108]. Managing these adverse events requires a different approach compared to traditional chemotherapy-induced toxicities. Individual patient characteristics, such as age, comorbidities, and genetic predispositions, can influence the severity of treatment-related toxicities[109]. Older patients and those with pre-existing conditions are particularly vulnerable to severe adverse effects, necessitating personalized treatment plans[110]. Regular monitoring of organ function and blood counts is crucial for detecting and managing adverse effects early. This includes renal, hepatic, and cardiac function assessments as well as complete blood counts. Further, adjusting drug doses or modifying treatment schedules can help manage severe toxicities while maintaining therapeutic efficacy. Collectively, tailoring treatment plans based on individual patient factors, such as age, comorbidities, and genetic predispositions, is critical for optimizing outcomes and minimizing adverse effects.

Strategies for monitoring and management: Effective management of patients undergoing combination therapies requires regular monitoring and prompt intervention. Routine clinical assessments, laboratory tests, and imaging are crucial for detecting toxicities early[111]. Frequent blood counts help identify myelosuppression, enabling timely dose adjustments or growth factor support. Implementing supportive care measures, such as anti-emetics for nausea and prophylactic antibiotics to prevent infections, is essential[112]. Balanced nutrition supports patient strength throughout treatment[113]. Tailoring treatment plans based on patient tolerance, including dose reductions and interruptions, can manage severe toxicities without undermining overall efficacy[114]. For instance, adjusting 5-FU doses can prevent complications while maintaining therapeutic benefits[115]. A multidisciplinary team approach comprising oncologists, nurses, pharmacists, and supportive care specialists ensures comprehensive care and effective toxicity management[116]. Educating patients about potential side effects and involving them in treatment decisions can improve adherence and prompt reporting of adverse effects. Additionally, psychological support plays a crucial role in helping patients cope with the emotional and physical demands of treatment[117].

Biomarker development: The development of predictive biomarkers is critical in selecting patients who are most likely to benefit from integrated treatment approaches, including chemotherapy, targeted therapy, and immunotherapy. Predictive biomarkers enable the customization of treatment plans based on the individual tumor biology of each patient. This personalized approach can optimize therapeutic efficacy and minimize unnecessary toxicity. By identifying patient’s responsiveness to specific therapies, biomarkers can help in stratifying patients and tailoring treatments, thereby improving clinical outcomes and survival rates[118]. Biomarkers can guide the selection of appropriate drug combinations and sequences, reducing the risk of adverse effects and enhancing the overall effectiveness of the treatment regimen. To date, several biomarkers have shown promise in predicting responses to various treatment modalities in GC (Table 2)[119-122].

Table 2 Predictive biomarkers in gastric cancer[119-122].

Biomarker	Clinical relevance	Alterations	Diagnosis	Targeted agents
HER2	Overexpressed in 15%-20% of GCs; associated with poor prognosis and aggressive disease	Gene amplification, protein overexpression	IHC, FISH	Trastuzumab, lapatinib
VEGF	Overexpression associated with angiogenesis and tumor progression	Protein overexpression	IHC, ELISA for serum VEGF levels	Bevacizumab, ramucirumab
MET	Amplification and overexpression linked to poor prognosis and aggressive behavior	Gene amplification, protein overexpression	IHC, FISH, NGS	MET inhibitors (e.g., crizotinib, onartuzumab)
PIK3CA	Mutations found in a subset of GCs; associated with activation of the PI3K/AKT pathway	Gene mutations	NGS, PCR-based mutation testing	PI3K inhibitors (e.g., buparlisib, alpelisib)
PD-L1	Linked to immune evasion by tumor cells; higher expression correlates with better response to immunotherapy	Protein overexpression	IHC	Pembrolizumab, nivolumab
CLDN18-ARHGAP26/ARHGAP	Fusions associated with a distinct subtype of GC; potential sensitivity to targeted therapy	Gene fusion	RNA sequencing, NGS	Ongoing research for specific targeted therapies
MSI-H/dMMR	Present in 15%-20% of GCs; associated with better prognosis and response to immunotherapy	Loss of mismatch repair protein function	PCR-based MSI testing, IHC for MMR proteins (MLH1, MSH2, MSH6, PMS2)	Pembrolizumab
FGFR2	Amplification seen in 5%-10% of GCs; linked to poor prognosis	Gene amplification	FISH, NGS	FGFR inhibitors (e.g., AZD4547, FPA144)
EBV	Found in approximately 10% of GCs; distinct molecular subtype with unique immune microenvironment	EBER positivity	ISH for EBER	Immunotherapy (ongoing research)
KRAS	Mutations present in a small percentage of GCs; linked to resistance to anti-EGFR therapies	Gene mutations	NGS, PCR-based mutation testing	Investigational KRAS inhibitors (e.g., AMG 510)

EBER: Epstein-Barr virus-encoded RNA; EBV: Epstein-Barr virus; EGFR: Epidermal growth factor receptor; FGFR2: Fibroblast growth factor receptor 2; FISH: Fluorescence in situ hybridization; GC: Gastric cancer; HER2: Human epidermal growth factor receptor 2; IHC: Immunohistochemistry; ISH: In situ hybridization; MET: Mesenchymal epidermal transition factor; MSI-H/dMMR: Microsatellite instability-high/mismatch repair deficient; NGS: Next-generation sequencing; PD-L1: Programmed death-ligand 1; VEGF: Vascular endothelial growth factor.

DISCUSSION

This systematic review provides a comprehensive synthesis of current evidence on the integration of immunotherapy with chemotherapy, radiotherapy, and targeted therapy in the management of GC. Collectively, the findings indicate that multimodal strategies incorporating ICIs significantly enhance clinical outcomes in selected patient subgroups compared with conventional regimens alone.

Notably, the combination of anti-PD-1/PD-L1 agents with cytotoxic chemotherapy has demonstrated superior OS and PFS. In the CheckMate-649 trial, nivolumab combined with chemotherapy significantly improved survival outcomes compared with chemotherapy alone[49]. Similar benefits were observed in the ATTRACTION-2 study, which established nivolumab as an effective treatment option for heavily pretreated advanced GC[47]. For HER2-positive tumors, the KEYNOTE-811 trial revealed that adding pembrolizumab to trastuzumab and chemotherapy markedly increased ORRs, underscoring the value of dual targeting of HER2 and PD-1 pathways[55]. Furthermore, the REGONIVO study reported encouraging results for the combination of regorafenib and nivolumab, suggesting that multi-kinase inhibitors can modulate the TME and potentiate immune activation[80]. The improved efficacy of chemo-immunotherapy combinations can be mechanistically attributed to the immunogenic properties of cytotoxic agents. These agents induce ICD, release neoantigens, and enhance DC activation, thereby amplifying the therapeutic impact of ICIs. Such mechanisms align with the superior outcomes observed in PD-L1-positive and MSI-high populations, as reported in trials such as CheckMate-649 and KEYNOTE-059[45]. Radiotherapy has also emerged as a promising adjunct to immunotherapy due to its ability to trigger systemic immune activation through the cGAS-STING signaling pathway, leading to the abscopal effect. Although direct evidence in GC remains limited, studies in other cancers such as PEMBRO-RT[65] and PACIFIC[123] support the synergistic potential of combining radiation and ICIs.

The integration of targeted therapy with immunotherapy is another rapidly evolving area. Foundational trials such as ToGA and RAINBOW[124] established the therapeutic relevance of trastuzumab and ramucirumab in defined molecular subtypes, and their combinations with ICIs are now being explored to leverage complementary mechanisms. Anti-VEGF agents like ramucirumab may normalize tumor vasculature and enhance immune cell infiltration, whereas HER2-targeted agents can increase antigen presentation, together fostering an immune-permissive TME.

Moreover, predictive biomarkers including PD-L1 CPS, MSI status, EBV association, and tumor mutational burden have consistently been correlated with response to immunotherapy[125]. Nevertheless, heterogeneity in PD-L1 testing methodologies and CPS thresholds continues to limit cross-trial comparability and clinical standardization.

CONCLUSION

GC remains a formidable challenge due to its aggressive nature, late diagnosis, and limited treatment options. The integration of immunotherapy with conventional treatments like chemotherapy, radiotherapy, and targeted therapies marks a significant advancement, offering new hope for improved outcomes. Immunotherapies such as pembrolizumab and nivolumab have shown promise, particularly when combined with chemotherapy and targeted therapies like HER2 inhibitors and VEGF inhibitors, enhancing OS and PFS in select patient populations. The synergistic potential of combining immunotherapy with radiotherapy and targeted therapies hinges on their ability to modulate the TME, enhance antigen presentation, and boost immune recognition. Clinical trials such as CheckMate-649, KEYNOTE-062, and REGONIVO underscore the benefits of these combinations, demonstrating improved efficacy and manageable safety profiles.

However, the complexity of combination therapies introduces increased toxicity, necessitating careful management and personalized treatment plans. The development of predictive biomarkers is crucial to tailor these therapies effectively, optimizing patient outcomes while minimizing adverse effects. As research progresses, these integrative approaches hold promise for transforming GC treatment, ultimately improving survival rates and quality of life for patients. The ongoing refinement of these strategies, supported by clinical evidence, underscores a hopeful trajectory towards more effective and personalized GC management.