Tumor microenvironment (TME) plays a pivotal role in progression and low responsiveness to chemotherapy of gastric cancer (GC). The cascade of events that culminate with a sustained and chronic activation of inflammatory pathways underlies gastric tumorigenesis. Infiltrating immune cells enrolling in crosstalk with cancer cells that regulate inflammatory and immune status, generating an immunosuppressive TME that influences the response to therapy. Here we discuss the role of TME and the activation of inflammatory pathways to comprehend strategies to improve drug response. Furthermore, we provides systematic insight the role of TME cytotypes and related signatures reinforcing the critical roles of TAMs and Tregs, in promoting GC chemoresistance and tumor progression.

The treatment paradigm for gastroesophageal cancers is evolving with immune checkpoint inhibitors (ICIs) as first-line therapy, making it crucial to understand their efficacy across patient subgroups, especially concerning PD-L1 expression. We performed a meta-analysis of Phase III randomized controlled trials targeting the effectiveness of ICIs with or without chemotherapy for advanced/metastatic HER2-negative gastroesophageal adenocarcinoma (GEA) or esophageal squamous cell carcinoma (ESCC). Kaplan-Meier (KM) curves of all-comer populations and subgroups according to reported PD-L1 cut-offs were extracted from published reports. Using KMSubtraction algorithm, unreported PD-L1 subgroup survival data were reconstructed by utilizing published KM survival curves. Thirteen first-line phase III RCTs involving 11,795 patients with GEA or ESCC were included. For GEA, ICI with or without chemotherapy showed longer OS in patients with PD-L1 combined positive score ≥1 (HR 0.77, 95 % confidence intervals [CI] 0.71-0.83 for ICI plus chemotherapy; HR 0.86, 95 %CI 0.75-1.01 for ICI alone) compared to chemotherapy alone, showing less benefits in low PD-L1 subgroups. ICI, with or without chemotherapy displayed survival benefits among PD-L1 tumor proportion score ≥1 % for ESCC (HR 0.62, 95 %CI 0.52-0.74 for ICI plus chemotherapy; HR 0.67, 95 %CI 0.54-0.84 for ICI alone) compared to chemotherapy alone. ICI combinations were similarly beneficial for Asian and global patients with GEA or ESCC. In conclusion, this meta-analysis, which includes unreported PD-L1 subgroups show benefit of ICIs with or without chemotherapy as a first-line treatment for advanced gastroesophageal cancers, particularly among patients with high PD-L1 expression.

Photoimmunotherapy with ASP-1929 (cetuximab conjugated to IRDye 700DX) and 690-nm red light has shown promising results, with a 43% objective response rate (ORR) in a phase IIa trial for recurrent head and neck squamous cell carcinoma. This study aimed to evaluate the safety and efficacy of combining photoimmunotherapy with nivolumab for advanced gastric cancer.

This phase Ib open-label, single-center trial investigated the combination of photoimmunotherapy with ASP-1929 and nivolumab in patients with unresectable EGFR-positive gastric adenocarcinoma after standard chemotherapy. The dose-escalation part aimed to determine the recommended dose of laser illumination energy under endoscopy, and the expansion part assessed the safety and efficacy at the determined dose. The primary endpoint was dose-limiting toxicity (DLT), and treatment response and adverse events were evaluated.

Between October 2019 and April 2022, 21 patients were enrolled. All patients had previously received at least two lines of chemotherapy, with six being refractory to anti-PD-1 therapy. No DLT was observed, and the recommended dose was 100 J/cm2. Two patients achieved a partial response, and ORR was 9.5%.

This study demonstrated that combining endoscopic photoimmunotherapy with nivolumab is safe and feasible for advanced gastric cancer.

The trial is registered in the Japanese Registry of Clinical Trials (identifier: jRCT2080224884, https://jrct.niph.go.jp/en-latest-detail/jRCT2080224884 ).

For gastric cancer patients, peritoneal metastasis poses a life-threatening risk due to the high incidence of treatment failure and disease recurrence. Conducting additional research aimed at identifying more efficacious strategies is imperative for enhancing treatment outcomes. This study examined the efficacy and safety of systemic chemotherapy plus a PD-1 inhibitor combination with intravenous or intraperitoneal bevacizumab for gastric cancer with peritoneal metastasis.

We conducted the open label, two-arm pilot study involved receiving albumin-bound paclitaxel (260 mg/m2, d1) plus S-1 (80 mg/m2, d1-14) combined with sintilimab (200 mg, d1) and bevacizumab (7.5 mg/m2, d1) (Arm A) intraperitoneally for moderate or large ascites or intravenously (Arm B) for non- or small ascites. The clinical trial was registered at the Chinese Clinical Trial Registry (ChiCTR2100048947 DATE: 2021-07-19).

Ten gastric cancer patients with peritoneal metastasis were enrolled in two arms (four in Arm A and six in Arm B) from August 19th, 2021 to June 1st, 2022. Until the end of the follow-up date, the mPFS for Arm A was 5.70 m (95% CI: 1.29-10.11), while Arm B had a mPFS of 9.07 m (95% CI: 3.79-14.35). The mOS for Arm A and Arm B was 8.43 (95% CI: 6.70-10.17) and 11.23 months (95% CI: 2.90-19.56). At least one common Grade 3/4 AE occurred in 25% of Arm A participants and 16.7% of Arm B patients.

Albumin-bound paclitaxel plus S-1 with a PD-1 inhibitor and intraperitoneal or intravenous bevacizumab was well tolerated in gastric cancer patients with peritoneal metastasis.

Evidence-guided regimens for advanced gastric cancer (AGC) in patients with performance status 2 (PS 2) are limited. Here, we proposed a structured therapeutic framework termed "performance status-matched strategy", and further conducted the APICAL-GC trial (NCT04278222). This open-label, single-arm phase II study evaluated the efficacy and safety of anlotinib combined with toripalimab among 24 treatment-naïve AGC patients with PS 2. The primary outcome was the objective response rate (ORR), with secondary endpoints including disease control rate (DCR), duration of response (DoR), progression-free survival (PFS), overall survival (OS), and safety profile. This trial met its prespecified endpoints, demonstrating an ORR of 58.3% (95%CI 36.6-77.9) with a DoR of 12.1 months (range: 1.43-48.5), and a DCR of 95.8% (95%CI 78.9-99.9). Median PFS reached 7.33 months (95%CI 3.83-17.1), while median OS was 15.9 months (95%CI 7.73-23.2). Treatment-related adverse events (TRAEs) of any grade occurred in 21 patients (87.5%), with grade-3 TRAEs observed in 7 patients (29.2%). No grade-4/5 TRAEs were reported. These findings provide a rationale for anlotinib plus toripalimab as a promising chemotherapy-free option for the first-line treatment of AGC patients with PS 2 under the performance status-matched strategy, showing comparable anticancer activity and a lower occurrence rate of TRAEs.

Whether continuing immunotherapy after progression in second-line settings of metastatic gastric cancer (MGC) remains unclear. Herein, we explored the efficacy of PD-1 inhibitors for MGC after progression on previous chemoimmunotherapy.

We retrospectively identified MGC patients who received oxaliplatin-based chemotherapy plus PD-1 inhibitor, with or without trastuzumab, as first-line treatment. The patients received treatment with or without PD-1 inhibitors beyond progression in patients with MGC were divided into treatment beyond progression (TBP) group and non-TBP (NTBP) group. The median progression free survival (PFS) and overall survival (OS) from the start of treatment after progression were assessed.

The mOS and mPFS in the TBP group was significantly longer than that in the NTBP group (mOS: 9.0 vs. 5.0 months, P = 0.011; mPFS: 4.3 vs. 2.7 months, P = 0.03). Moreover, TBP was an independent prognostic factor for both PFS and OS in multivariate analysis. In the subgroup analysis, patients who were male, had a favorable ECOG (0-1), classified into diffuse histologic subtype and achieved disease control in the prior chemoimmunotherapy, might be more likely to benefit from continuing immunotherapy compared to discontinuation beyond progression.

PD-1 inhibitors based therapeutic strategy may be a reasonable option in second-line setting for MGC who progressed on prior immunotherapy. Further larger prospective trials are warranted to validate these findings.

Introduction: Peritoneal metastasis (PM) is the most common site of recurrence following curative resection for advanced gastric cancer (GC). Along with disease progression, it can lead to complications such as intestinal obstruction, hydronephrosis, obstructive jaundice, and ascites, significantly impairing the patient's quality of life. Therefore, peritoneal metastasis is considered a critical target for treatment. In general, these patients are treated with systemic chemotherapy; however, the therapeutic effect is often limited due to the anticancer agents' poor penetration into the peritoneal cavity. We aim to identify factors associated with the best overall survival (OS) in GC patients with peritoneal metastasis. Methods: Patients with advanced GC who were diagnosed as having macroscopic PM or positive peritoneal cytology by staging laparoscopy were enrolled. We introduced intraperitoneal Paclitaxel (IP-PTX) combined with S-1 plus oxaliplatin (SOX). Gastrectomy with lymph node dissection was performed as conversion surgery when the PM showed an excellent response. Results: Ninety-six patients received IP-PTX + SOX, with a median of 16 courses. The 1- and 5-year OS rates were 70.2% and 24.5%, respectively, with a mean survival time (MST) of 20.0 months. No chemotherapy-related mortality was observed. Conversion surgery was performed in 44 patients (45.8%), with a 1-year OS rate of 100%. Conclusions: Combination chemotherapy using the IP-PTX + SOX regimen is highly effective and is recommended as induction chemotherapy for patients with PM from GC. Conversion gastrectomy should be considered following an excellent response, particularly in patients with peritoneal cancer index (PCI) scores below 20.

Immune checkpoint inhibitors (ICIs) are becoming more prominent in the treatment of gastric cancer (GC). However, predictive biomarkers of response to ICIs in HER2-negative patients remain incompletely understood.

A total of 47 patients diagnosed with HER2-negative advanced GC who underwent ICI regimens were eligible for this study. Plasma samples with paired white blood cells prior to treatments were collected from these 47 patients. Variations of circulating tumor DNA (ctDNA) was evaluated by next-generation sequencing followed by its significance analysis.

A total of 658 somatic mutations involving 203 genes were identified in all ctDNA. Mutations in MEN1, MLH1, CEBPA, ATR, GNAQ, and FOXL2 genes were more frequent in responders (P < 0.05). Compared with wild-type patients, patients with CEBPA or IRS2 mutations had prolonged median progression-free survival (mPFS, P = 0.0056). Patients with co-occurring mutations in IRS2/CEBPA, IRS2/POLD1, TP53/PIK3CA, or POLD1/CEBPA had longer mPFS compared with others (P = 0.003; 0.006; 0.0166; 0.0315; respectively). Both alteration of CDKN2A alone and co-mutations with MSH6 were significantly associated with superior overall survival (OS, P = 0.0289; 0.0355; respectively). In addition, higher on-treatment ctDNA concentration or variant allele frequency (VAF) were associated with poorer response (P < 0.05). Additionally, the increased molecular alterations of POLE, FGFR2 and MDC1 seemed to indicate the acquired resistance to ICIs.

Variation signatures captured by ctDNA as well as the kinetics of ctDNA could predict the clinical benefits of ICB in HER2-negative GC patients, which was worth further validated in large cohort.

Gastric cancer (GC) is one of the primary contributors to cancer-related mortality on a global scale. It holds a position within the top five most prevalent malignancies both in terms of occurrence and fatality rates. Immunotherapy, as a breakthrough cancer treatment, brings new hope for GC patients. Various biomarkers, such as the expression of programmed death ligand-1 (PD-L1), the microsatellite instability (MSI) status, tumor mutational burden (TMB), and Epstein-Barr virus (EBV) infection, demonstrate potential to predict the effectiveness of immunotherapy in treating GC. Nevertheless, each biomarker has its own limitations, which leads to a significant portion of patients continue to be unresponsive to immunotherapy. With the understanding of the tumor immune microenvironment (TIME), genome sequencing technology, and recent advances in molecular biology, new molecular markers, such as POLE/POLD1mutations, circulating tumor DNA, intestinal flora, lymphocyte activation gene 3 (LAG-3), and lipid metabolism have emerged. This review aims to consolidate clinical evidence to offer a thorough comprehension of the existing and emerging biomarkers. We discuss the mechanisms, prospects of application, and limitations of each biomarker. We anticipate that this review will open avenues for fresh perspectives in the investigation of GC immunotherapy biomarkers and promote the precise choice of treatment modalities for gastric cancer patients, thereby advancing precision immuno-oncology endeavors.

This study aims to comprehensively evaluate the hematologic toxicity profiles, toxicity spectrum, and safety rankings of immune checkpoint inhibitors (ICIs) used for digestive system tumors. The PubMed, Cochrane Library, Web of Science, and Embase databases were systematically searched from inception to August 2024 to identify randomized controlled trials (RCTs). The primary outcome was anemia, while secondary outcomes included neutropenia, neutrophil count decreased, thrombocytopenia, platelet count decreased, leukopenia, white blood cell (WBC) count decreased, lymphocyte count decreased, and febrile neutropenia (FN). Subgroup analyses were performed based on tumor type, country category, study phase, ICI regimen, control group, chemotherapy regimen, ICI plus different chemotherapy regimens. Two reviewers independently selected the studies, extracted data according to pre-specified criteria, and assessed the risk of bias using the Cochrane Collaboration risk of bias tool. RevMan 5.4 software was utilized to visualize the risk of bias assessments. Stata 16.0 was used to conduct network meta-analysis, sensitivity analysis and meta-regression. 25 phase II and III RCTs (n = 15216) were included. The general safety of ICIs ranked from high to low for grade 1-5 anemia were as follows: avelumab, nivolumab, pembrolizumab, sintilimab, camrelizumab, and tislelizumab. For grade 3-5 anemia, the general safety profile of the ICIs were as follows, from highest to lowest: avelumab, nivolumab, pembrolizumab, sintilimab, and camrelizumab. Compared to chemotherapy, treatment-related hematologic toxicities with ICIs occurred primarily in grade 1-5 anemia, neutropenia, thrombocytopenia, leukopenia, and WBC count decreased. Taking ICI monotherapy, nivolumab plus ipilimumab were generally safer than taking chemotherapy, one ICI drug with chemotherapy, or two ICI drugs with chemotherapy. In terms of grade 1-5 hematologic toxicities, tislelizumab had the highest risk of neutropenia and leukopenia; the primary treatment-adverse events (AEs) for sintilimab was neutrophil count decreased and WBC count decreased; the primary treatment-related AE associated with nivolumab was platelet count decreased; camrelizumab posed the highest risk for lymphocyte count decreased. In terms of grade 3-5 hematologic toxicities, pembrolizumab was predominantly linked to neutropenia; sintilimab showed the greatest risk for neutrophil count decreased, platelet count decreased, and lymphocyte count decreased; avelumab was most associated with WBC count decreased. FN primarily manifested as grade 3-5, with camrelizumab having the highest risk. Among agents used in gastric or gastroesophageal junction cancer, avelumab demonstrated the most favorable safety profile for anemia. Each treatment regimen has its unique safety profile. Early identification and management of ICI-related hematologic toxicities are essential in clinical practice.Systematic Review Registration: PROSPERO CRD42024571508.

Immune checkpoint inhibitors (ICIs) + chemotherapy became standard her2-GC first line treatment.

The aim of this study is to investigate whether ICIs + chemo provides benefit for patients with low programmed death-ligand 1 (PD-L1) expression.

This study is a systematic review and meta-analysis.

We searched PubMed, Embase, Web of Science, and Cochrane Library as well as the 2019 to 2024 Annual Meetings of the European Society for Medical Oncology, the American Association for Cancer Research, the American Society of Clinical Oncology (ASCO), and the ASCO Symposium on Gastrointestinal Oncology (ASCO-GI) and the ClinicalTrials.gov database.

This systematic review included phase III randomized controlled trials comparing first-line immunotherapy combined with chemotherapy versus chemotherapy alone in advanced gastric cancer. KMSubtraction was used to estimate survival data for those trials that did not report data for the PD-L1 low-expression population.

We included a total of nine randomized clinical trials. In patients with combined positive score (CPS) < 1 and CPS < 5, monoclonal antibody + chemotherapy did not show an improvement in overall survival (OS) or progression-free survival (PFS) (CPS < 1 OS: hazard ratio (HR) = 0.91, 95% CI: 0.77-1.08; PFS: HR = 0.88, 95% CI: 0.73-1.07. CPS < 5 OS: HR = 0.92, 95% CI: 0.79-1.08; PFS: HR = 0.78, 95% CI: 0.53-1.14). However, in trials using dual antibodies, patients with PD-L1 CPS < 5 achieved improvements in PFS (HR = 0.64, 95% CI: 0.52-0.80). In trials using tumor area positivity (TAP) scoring, the subgroup with TAP < 5% did not achieve benefits in OS or PFS from immunotherapy plus chemotherapy (OS: HR = 0.92, 95% CI: 0.75-1.13; PFS: HR = 0.91, 95% CI: 0.74-1.13).

Our study results indicate that in the first-line treatment of advanced gastric cancer, monoclonal antibody combined with chemotherapy does not provide a survival benefit compared to chemotherapy alone for patients with low PD-L1 expression. However, it is noteworthy that in the COMPASSION-15 trial, patients with CPS < 5 achieve significant improvements in OS and PFS, which may be related to the bispecific antibodies and needs to be validated by further studies.

This study was registered in PROSPERO (CRD42024568972).

Combination treatment with an anti-programmed cell death-1 (PD-1) antibody, an immune checkpoint inhibitor (ICI), and chemotherapy is the standard treatment for patients with HER2-negative advanced gastric/esophagogastric cancer (AGC). ICI re-administration has been reported to have a clinical benefit for patients with lung cancer or melanoma. However, data on patients with AGC have not yet been collected. We plan to conduct a prospective, multicenter, observational NIVO RETURNS study to evaluate the efficacy and safety of nivolumab monotherapy re-administration in patients with AGC refractory to initial anti-PD-1 or anti-programmed cell death ligand-1 (PD-L1) antibody treatment. Patients who have achieved clinical benefits (complete response, partial response, or stable disease for ≥ 6 months) from prior treatment, including anti-PD-1/PD-L1 therapy, will be included. The primary endpoint will be the objective response rate to nivolumab re-administration. We anticipate that our findings will contribute to the improvement of survival outcomes as later-line treatment for AGC.Clinical trial registration: UMIN000050515, UMIN000051044.

Previous trials have revealed better treatment efficacy of programmed cell death 1 (PD-1) inhibitors combined with chemotherapy as first-line treatments than chemotherapy alone in advanced gastric cancer (GC) patients, but real-world evidence is still lacking. Hence, this real-world study aimed to investigate the efficacy and safety of PD-1 inhibitors plus chemotherapy as first-line treatments compared with chemotherapy alone in advanced GC patients.

In total, 102 advanced GC patients were allocated into a combination group (receiving chemotherapy combined with a PD-1 inhibitor as a first-line treatment) (n = 48) or a chemotherapy group (receiving chemotherapy only as a first-line treatment) (n = 54) according to their actual treatment regimens.

The objective response rate (ORR) was greater in the combination group than in the chemotherapy group (25.0 % versus 9.3 %, P = 0.033), whereas the disease control rate (DCR) was not different between the groups (83.3 % versus 66.7 %, P = 0.054). Progression-free survival (PFS) was prolonged in the combination group than in the chemotherapy group (P = 0.018). The median (95 % confidence interval) PFS was 19.7 (12.2-27.2) months in the combination group and 16.5 (7.3-25.7) months in the chemotherapy group. Multivariate logistic regression analyses revealed that PD-1 inhibitors combined with chemotherapy were independently associated with an increased ORR (odds ratio: 4.180, P = 0.024), increased DCR (odds ratio: 2.928, P = 0.049), and prolonged PFS (hazard ratio: 0.388, P = 0.030). No difference was found in total or each specific grade III-IV adverse reaction between the groups (all P > 0.05).

Treatment with a PD-1 inhibitor plus chemotherapy as a first-line treatment shows better treatment efficacy with similar safety to that of chemotherapy alone in advanced GC patients.

The incorporation of immunotherapy has transformed the treatment landscape for advanced, unresectable, or metastatic gastroesophageal cancers (GECs), with improved survival outcomes. These improvements in outcomes for advanced GECs have led to clinical trials evaluating the role of immunotherapy in patients with resectable early-stage GECs. However, there remains a high burden of morbidity and mortality, and ongoing trials utilizing novel immunotherapy agents and combinations are underway. This review summarizes the findings of previous and ongoing clinical trials related to immunotherapy for patients with early- and late-stage GECs.

In this prospective, open-label, exploratory study (RENMIN-213), patients with previously untreated, HER2-negative, advanced G/GEJ adenocarcinoma with signet ring cell carcinoma or peritoneal metastasis were enrolled to receive eight cycles of apatinib, tislelizumab, and chemotherapy every 3 weeks, with a maintenance therapy with apatinib plus tislelizumab for a maximum of 1 year. Homogeneous patients receiving immune checkpoint inhibitors combined with chemotherapy at the same time were deemed as the control group for efficacy. The primary endpoint was progression-free survival. Secondary endpoints were objective response rate, disease control rate, duration of response, overall survival, biomarkers, health-related quality of life, and safety. A total of 33 patients [median (range) age, 60 (32-72) years; 21 (63.6%) male; 11 (33.3%) signet ring cell carcinoma; 30 (90.9%) peritoneal metastasis] were enrolled and deemed evaluable for efficacy analysis. Of these patients, 32 (97%) were without disease progression, of whom 1 (3.0%) patient had complete response and 18 (54.6%) had partial response. Six patients (18.2%) were able to undergo surgery after treatment. After propensity score matching, the median progression-free survival was 10.17 months (95% confidence interval, 7.13-13.21) in the apatinib combined with tislelizumab and chemotherapy group, as compared with 6.0 months in the immune checkpoint inhibitor combined with chemotherapy group. The median duration of response increased from 4.5 to 8.7 months. The objective response rate increased from 33.3% to 54.6%, and the disease control rate increased from 87.9% to 97.0%. Treatment-related grade 3 or higher adverse events for evaluable patients occurred in 11 patients (33.3%), and patients' health-related quality of life improved after treatment.

Gastric cancer (GC) represents a global health-care challenge. Recent progress in immunotherapy has elicited attracted considerable attention as a viable treatment option through modulating the host immune system and unleashing pre-existing immunity, which has profoundly revolutionized oncology, especially GC. Nonetheless, low clinical response and intrinsic and acquired resistance remain persistently challenging. The microenvironment of GC comprising multifarious stromal cell types has remarkable immunosuppressive elements that may impact the efficacy of immunotherapy. Immunosenescence is increasingly regarded as a factor that contributes to cancer development, remodels the tumor microenvironment and affects the efficacy of immunotherapy. Natural products are at the forefront of traditional medicine. Senotherapeutics is a class of drugs and natural products capable of delaying, preventing, or reversing the senescence process (i.e., senolytics) or suppressing senescence-associated secretory phenotype (i.e., senomorphics). Emerging evidence supports that natural products can improve the efficacy of existing immunotherapy and expand their indications in GC mainly based upon remodeling the immunosuppressive microenvironment and reversing immunosenescence. The review provides an integrated review of previously reported and ongoing clinical trials with immunotherapeutic regimens in GC and discusses current challenges. Next, we focus on natural compounds that exert anti-GC functions and possess immunomodulatory properties. More attention is paid to the potential of these natural compounds in modulating the immune microenvironment and immunosenescence. Lastly, we discuss the nanomedicine that can overcome the deficiencies of natural products. Altogether, our review suggests the enormous potential of natural compounds in GC immunotherapy, and provides an important direction for future research.

Claudin 18 isoform 2 (CLDN18.2) is a potential therapeutic target in gastric cancer (GC). However, combining chemotherapy with anti-CLDN18.2 antibodies has shown limited efficacy in CLDN18.2-positive GC, and chemotherapy-induced changes in the tumor microenvironment (TME) remain unclear.

This study analyzed 37 GC samples, including 11 CLDN18.2-positive cases, using single-cell RNA sequencing and multiplex immunofluorescence to assess chemotherapy-driven TME changes in CLDN18.2-positive GC.

In chemotherapy-treated CLDN18.2-positive GC, cytotoxic natural killer (NK) cells displayed antibody-dependent cytotoxicity (ADCC)-related genes at lower levels than in untreated CLDN18.2-positive GC, while regulatory T cells (Tregs) and tumor-associated macrophages (TAMs) showed TGFB1 expression at higher levels. Additionally, NK cells, Tregs, and TAMs were more abundant in chemotherapy-treated than untreated CLDN18.2-positive GC. These chemotherapy-induced changes were absent in CLDN18.2-negative GC. Cell-cell interaction analysis identified unique interactions in chemotherapy-treated CLDN18.2-positive GC, including CCL5-CCR5 signaling between cytotoxic NK cells (Sender) and effector Tregs (Receptor) and TGFB1-TGFBR signaling between effector Tregs (Sender) and TAMs (Receptor). Cytotoxic NK cells expressed CCL5 at higher levels, CCR5-positive Tregs were more prevalent, and TAMs exhibited higher TGF-β receptor signature scores in chemotherapy-treated than untreated CLDN18.2-positive GC.

Our findings indicate that chemotherapy can drive immunosuppressive TME modifications specific to CLDN18.2-positive GC.

The current biomarkers for immune checkpoint inhibitor (ICI) therapy have several limitations, and new ones are being explored. Retinoblastoma-binding protein 8 (RBBP8) is associated with tumor-infiltrating immune cells (TIIC) and immune checkpoint molecules. Therefore, RBBP8 may serve as a novel biomarker for ICI therapy. Thus, in this study, we investigated the relationship between RBBP8 expression and the tumor immune environment in 58 patients with pathologic T3-4 gastric cancer who underwent radical gastrectomy. Immunohistochemistry of primary tumor specimens was performed to evaluate RBBP8, TIIC, and programmed cell death ligand 1 expression. Kaplan-Meier survival and prognostic factor analyses were also performed using Cox proportional hazards regression models. Patients were divided into RBBP8 high (HG, n=29) and low (LG, n=29) expression groups, using the median RBBP8 expression as the cutoff. The LG had a significantly worse overall survival rate than the HG (log-rank test, P =0.029). Furthermore, the overall survival rate of patients in LG who were treated with ICI (n=7) was worse than that of those in HG (n=9; log-rank P =0.005). Multivariate analysis identified extensive lymph node metastasis and low RBBP8 expression as independent prognostic factors. The HG and LG showed no significant difference in the number of TIICs; however, there was a difference in the number ratios of CD4+/CD8+ ( P =0.012) and CD4+/CD3+ cells ( P <0.001). Therefore, RBBP8 expression in patients with advanced gastric cancer is a prognostic marker that affects the proportion of CD4+ T-cell infiltration and may also be a biomarker for predicting ICI treatment response.

Gastric cancer remains a major health challenge worldwide, with nearly 1 million new cases annually contributing to more than 650 000 deaths. Epidemiologically, gastric cancer shows substantial geographical variation in incidence, with higher rates in Asia, South America, and eastern Europe, and a rapid increase in early-onset cases among people younger than 50 years. Key risk factors for gastric cancer include Helicobacter pylori infection, diet, obesity, smoking, and genetic predisposition. Early detection through comprehensive diagnostic procedures is crucial for optimising treatment outcomes. Standard treatment approaches for locally advanced gastric cancer include surgical resection, particularly D2 lymphadenectomy, complemented by chemotherapy and radiotherapy. There is increasing implementation of minimally invasive surgical techniques for operable disease and integration of immune checkpoint inhibitors and targeted therapies for advanced stages. Emerging therapies, such as novel targeted treatments and next-generation immunotherapies, show promise in improving survival and quality of life. Future directions in the management of gastric cancer focus on precision medicine, continued advancement in immunotherapy, novel early detection methods, and a multidisciplinary approach to care. These strategies aim to enhance the overall effectiveness of treatment and prognosis worldwide.

Immune checkpoint inhibitors (ICIs) have been associated with an increased risk of cardiovascular and thromboembolic events. However, the incidence of cardiovascular and thromboembolic events associated with ICIs in gastroesophageal cancers is unknown.

We performed a propensity score-matched cohort study using the TriNetX Analytics Network database, which comprises de-identified data from over 130 participating healthcare institutions. Patients who received ICI and chemotherapy were compared with those who received only chemotherapy. The primary outcomes were cardiovascular events including pericarditis, myocarditis, heart failure, myocardial infarction, ischemic stroke, atrial fibrillation, conduction disorders as well as venous thromboembolism (VTE) within 1-year of ICI or chemotherapy. We matched the cohorts based on predetermined variables including demographics, metastatic disease, chemotherapy, underlying comorbidities, and the use of cardiovascular and lipid-lowering medications.

We identified 1,448 patients who received ICI and chemotherapy and 11,966 patients who received chemotherapy only. After matching, 1,425 patients remained in each cohort. The mean age was 63.1 ± 12.7 years in the ICI and chemotherapy cohort and 62.9 ± 12.1 years in the chemotherapy-only cohort. ICI was associated with a higher incidence of pericarditis (45.6 vs. 30.9 cases per 1000 patient-years; HR 1.51 [95% CI 1.03-2.22]) and VTE (102.5 vs. 75.1 cases per 1000 patient-years; HR 1.40 [95% CI 1.09-1.80]). The incidence of other cardiovascular outcomes were similar between the two cohorts.

In this cohort study, the use of ICI and chemotherapy was associated with an approximately 40-50% increased risk of pericarditis and VTE than patients on chemotherapy only.

Lymphocyte-to-C-reactive protein ratio (LCR) is a useful biomarker for predicting the prognosis of various cancers. This study examined the effect of LCR on the oncological prognosis of patients with gastric cancer who underwent curative resection at our institution and considered the mechanisms involved.

In this retrospective cohort study, 258 subjects were selected from the medical records of patients who underwent curative resection for gastric cancer at Yokohama City University between 2005 and 2020. The LCR was calculated using the following formula: LCR=lymphocyte count (number/μl)/C-reactive protein (mg/dl).

The cutoff value for LCR was set at 9,000, and 258 patients were classified into the LCR-low (<9,000) (58 patients) and LCR-high (>9,000) (200 patients) groups. The overall survival (OS) and recurrence-free survival (RFS) rates of the two groups were compared. The 5-year overall survival rate was 54.2% in the LCR-low group and 75.2% in the LCR-high group (p<0.001), and a multivariate analysis showed that it was a useful prognostic factor [hazard ratio (HR)=1.744, 95% confidence interval (CI)=1.009-3.014, p=0.046]. In addition, with regard to RFS, there was a significant difference in the 5-year RFS between the LCR-low group (50.4%) and the LCR-high group (72.3%) (p<0.001). Regarding the comparison of the postoperative clinical course between the two groups, the peritoneal recurrence rate was 24.1% in the LCR-low group and 7.5% in the LCR-high group (p<0.001).

Preoperative LCR is a useful prognostic factor for predicting the oncological prognosis of patients with gastric cancer undergoing curative resection. Thus, the LCR may be a useful tool for the treatment and perioperative management of patients with gastric cancer.

This study aims to assess the therapeutic efficacy and safety of nivolumab combined with chemotherapy as a first-line treatment for advanced or metastatic gastric cancer, specifically comparing the outcomes of oxaliplatin-based versus albumin-bound paclitaxel (nab-paclitaxel)-based therapies.

We retrospectively analyzed 93 patients with advanced gastric cancer or gastroesophageal junction adenocarcinoma treated at the First Medical Center of Chinese PLA General Hospital from September 2017 to November 2022. Patients were categorized into the nivolumab + oxaliplatin (N-OX group) or nivolumab + nab-paclitaxel (N-AP group) based on the chemotherapy regimen. Progression-free survival (PFS), objective response rate (ORR), disease control rate (DCR), and safety were evaluated as endpoints.

At the end of the follow-up period on September 31, 2023, we reported an ORR of 65.6% and DCR of 95.7% across all patients. The median PFS was 8.4 months, with no significant difference between the N-OX and N-AP groups (median, 7.8 vs 9.5 months; P = 0.450). Notably, patients with diffuse gastric cancer in N-AP group showed a 44.7% reduction in tumor progression risk compared with the N-OX group (P = 0.046). The overall safety profile was acceptable in two groups.

Our study suggested that nivolumab combined with chemotherapy was effective and safe as a first-line intervention for advanced gastric cancer. While both oxaliplatin and nab-paclitaxel regimens showed similar efficacy, the nab-paclitaxel may offer additional benefits for patients with diffuse gastric cancer. Further research is encouraged to confirm these findings and refine treatment strategies.

PARP inhibitors, effective in BRCA-mutated cancers, show potential in gastric cancer (GC) where homologous recombination defects (e.g., BRCA1/2 mutations) are common. Olaparib, a PARP inhibitor, upregulates PD-L1, suggesting synergy with PD-1 inhibitors for enhanced GC therapy.

Using CCK-8 screening of 867 drugs, olaparib demonstrated potent GC cell inhibition. Western blot and qRT-PCR assessed PD-L1, c-MYC, COX-2, and NF-κB pathway proteins (p65/p-p65). Functional assays (Transwell, wound healing, colony formation) evaluated olaparib's effects on GC cell proliferation, migration, and invasion. A GC mouse model tested olaparib combined with anti-PD1. TCGA and Kaplan-Meier analyzed PARP expression-prognosis correlations.

Olaparib suppressed GC cell proliferation, migration, and invasion in vitro. Western blot revealed upregulated c-MYC, COX-2, p65, p-p65, and PD-L1, confirmed by qRT-PCR for PD-L1. Low PARP expression correlated with better GC patient survival. In vivo, olaparib synergized with anti-PD1 to enhance tumor suppression.

Olaparib activates the NF-κB/c-MYC pathway to elevate PD-L1, supporting its combination with PD-1 inhibitors as a promising GC therapeutic strategy.

Gastric cancer, including gastroesophageal junction cancer, is one of the most commonly diagnosed cancers worldwide, with high mortality. Sugemalimab is a fully human anti-programmed death-ligand 1 (PD-L1) antibody. The combination of sugemalimab and chemotherapy showed promising antitumor activity and safety in a phase 1b study among patients with treatment-naive, unresectable, locally advanced or metastatic gastric or gastroesophageal junction adenocarcinoma. This combination was further evaluated in the GEMSTONE-303 phase 3 trial.

To evaluate the efficacy of sugemalimab in combination with capecitabine and oxaliplatin (CAPOX) compared with placebo plus CAPOX as first-line treatment for patients with unresectable locally advanced or metastatic gastric or gastroesophageal junction adenocarcinoma with PD-L1 combined positive score (CPS) of 5 or greater.

GEMSTONE 303 is a phase 3, randomized, double-blind, placebo-controlled study conducted at 54 sites in China that enrolled patients from April 9, 2019, through December 29, 2021, with follow-up to July 9, 2023. A total of 479 eligible patients with unresectable locally advanced or metastatic gastric or gastroesophageal junction adenocarcinoma with PD-L1 CPS of 5 or greater who did not receive any prior systemic therapy were randomized.

Patients received sugemalimab (1200 mg intravenously) (n = 241) or placebo (n = 238) every 3 weeks for up to 24 months, plus CAPOX every 3 weeks for up to 6 cycles.

Primary outcomes were overall survival and investigator-assessed progression-free survival.

Baseline characteristics were well balanced between the 2 groups. Most patients were male (71.4% in sugemalimab group, 74.8% in placebo group). Median follow-up was 25.1 months in the sugemalimab group and 26.3 months in the placebo group. The sugemalimab group demonstrated significant improvements in overall survival (median, 15.6 months [95% CI, 13.3-17.8] vs 12.6 months [95% CI, 10.6-14.1]; hazard ratio, 0.75 [95% CI, 0.61-0.92]; P = .006) and progression-free survival (median, 7.6 months [95% CI, 6.4-7.9] vs 6.1 months [95% CI, 5.1-6.4]; hazard ratio, 0.66 [95% CI, 0.54-0.81]; P < .001). Grade 3 or higher treatment-related adverse events occurred in 53.9% of patients in the sugemalimab group and 50.6% in the placebo group.

Sugemalimab plus chemotherapy significantly prolonged overall survival and progression-free survival with a manageable safety profile in previously untreated patients with unresectable locally advanced or metastatic gastric or gastroesophageal junction adenocarcinoma.

ClinicalTrials.gov Identifier: NCT03802591.

The treatment of gastric cancer remains highly challenging, particularly in cases of unresectable locally advanced or metastatic disease. Although chemotherapy and immunotherapy have shown some efficacy in such patients, significant limitations persist in extending survival and enhancing safety. To address these challenges, we designed an innovative first-line quadruple conversion therapy regimen that integrates a programmed cell death protein 1 (PD-1) inhibitor with chemotherapy, and we successfully implemented this therapy regimen in the treatment of a patient with unresectable locally advanced gastric adenocarcinoma.

We report the case of a 55-year-old male who was diagnosed with unresectable locally advanced gastric adenocarcinoma and presented with intermittent epigastric pain and multiple lymph node metastases in the abdominal cavity, with the metastasis being notably large in size. The tumor tissue was negative for human epidermal growth factor receptor 2 by immunohistochemistry. Considering the patient's status, the multidisciplinary team decided to administer sintilimab in combination with albumin-bound paclitaxel (nab-paclitaxel), S-1, and oxaliplatin as a quadruple drug conversion therapy. After 4 cycles of conversion therapy, the patient's epigastric pain was significantly alleviated, his stool color normalized, the volume of the primary tumor and lymph node metastases was markedly reduced, and the tumor marker levels decreased to within the normal range. The patient subsequently underwent laparoscopic total gastrectomy with abdominal lymph node dissection, and postoperative pathological biopsy revealed a pathological complete response and R0 resection, after which the patient recovered to an excellent physical status.

To the best of our knowledge, this is the first reported case of unresectable locally advanced gastric adenocarcinoma successfully treated with quadruple therapy with a PD-1 inhibitor and chemotherapy as a first-line conversion regimen. This first-line conversion therapy with the quadruple regimen may be effective and safe for unresectable locally advanced gastric adenocarcinoma.

We developed and refined an S-1 dosage formula based on renal function, sex, and body surface area (BSA) to achieve the target area under the concentration-time curve of 5-fluorouracil in two prospective pharmacokinetic studies. The clinical validity of the refined formula (BBT formula) was evaluated using data from the two phase III trials of fist-line chemotherapy including S-1 for advanced gastric cancer, which demonstrated that overall survival and progression-free survival tended to be shorter in patients whose S-1 standard dose, based on BSA alone, was lower than that determined using the BBT formula.

Chemo-naïve patients with HER2-negative advanced gastric or gastroesophageal junction cancer, whose standard S-1 dose is lower than that determined using the BBT formula, receive S-1 at an increased dose based on the BBT formula plus oxaliplatin (130 mg/m2) and nivolumab (360 mg/body). The primary endpoint is the incidence of dose-limiting toxicity in six patients in the phase I part and the proportion of patients requiring S-1 dose reduction in a total of 20 patients, expecting 30% and rejecting 50% with an alpha error of 0.1 and beta error of 0.2. The secondary endpoints are adverse events, relative dose intensity, response rate, disease control rate, progression-free survival, and overall survival. A correlation study is conducted to investigate the immune profiles associated with efficacy.

This phase I/II trial evaluates the safety and efficacy of S-1 at increased doses, determined by the BBT formula, in combination with oxaliplatin and nivolumab in patients with HER2-negative advanced gastric cancer, whose standard dose of S- 1 is lower than the dose recommended dose by the BBT formula.

This study was approved by the University of Tokyo Clinical Research Review Board (URL: https://www.ut-crescent.jp/patients/chiken_jisshi/ , review number: 2022529SP) and was initiated at 19 institutions in June 2023 (registered as jRCTs031230127).

This study conducted a network meta-analysis to evaluate and rank the safety and efficacy of programmed cell death protein-1 (PD-1) inhibitors for patients with advanced gastric or gastroesophageal junction cancer (GC/GEJC).

A systematic search was conducted in PubMed, Embase, and Cochrane Library databases to compare the efficacy and safety of different treatment regimens, including overall survival (OS), progression-free survival (PFS), objective response rate (ORR), and treatment-related adverse events (TRAEs) in patients with advanced GC/GEJC.

A total of six RCT studies were ultimately included in the analysis, involving 6,294 patients. Among them, 256 patients received PD-1 inhibitor monotherapy (pembrolizumab), 3,029 patients received a PD-1 inhibitor plus chemotherapy (1,047 with pembrolizumab, 1,154 with nivolumab, 327 with sintilimab, and 501 with tislelizumab), and 3,009 received either chemotherapy or chemotherapy plus placebo. Sintilimab plus chemotherapy had the highest SUCRA value for OS (85.2%), while nivolumab plus chemotherapy had the highest SUCRA values for both PFS and ORR (96.8% and 82.9%). Four PD-1 inhibitors plus chemotherapy significantly improved median OS and ORR compared with chemotherapy. Sintilimab plus chemotherapy, pembrolizumab plus chemotherapy, and nivolumab plus chemotherapy significantly improved median PFS compared with chemotherapy. For TRAEs of grade 3 or worse, pembrolizumab monotherapy had the highest SUCRA value. Tislelizumab plus chemotherapy, as well as sintilimab plus chemotherapy, did not increase the overall incidence of TRAEs and the incidence of grade 3 or worse TRAEs.

In the first-line treatment of advanced GC/GEJC, PD-1 inhibitors plus chemotherapy have been demonstrated to significantly improve OS, PFS, and ORR compared with chemotherapy. Among them, sintilimab plus chemotherapy achieved the highest SUCRA value for OS, and nivolumab plus chemotherapy achieved the highest SUCRA values for PFS and ORR. Regarding safety, tislelizumab plus chemotherapy and sintilimab plus chemotherapy did not increase the overall incidence of TRAEs and the incidence of grade 3 or worse TRAEs, with good tolerability and safety.

A spatially resolved, niche-level analysis of tumour microenvironments (TME) can provide insights into cellular interactions and their functional impacts in gastric cancers (GC).

Our goal was to translate the spatial organisation of GC ecosystems into a functional landscape of cellular interactions involving malignant, stromal and immune cells.

We performed spatial transcriptomics on nine primary GC samples using the Visium platform to delineate the transcriptional landscape and dynamics of malignant, stromal and immune cells within the GC tissue architecture, highlighting cellular crosstalks and their functional consequences in the TME.

GC spatial transcriptomes with substantial cellular heterogeneity were delineated into six regional compartments. Specifically, the fibroblast-enriched TME upregulates epithelial-to-mesenchymal transformation and immunosuppressive response in malignant and TME cells, respectively. Cell type-specific transcriptional dynamics revealed that malignant and endothelial cells promote the cellular proliferations of TME cells, whereas the fibroblasts and immune cells are associated with procancer and anticancer immunity, respectively. Ligand-receptor analysis revealed that CCL2-expressing fibroblasts promote the tumour progression via JAK-STAT3 signalling and inflammatory response in tumour-infiltrated macrophages. CCL2+ fibroblasts and STAT3-activated macrophages are co-localised and their co-abundance was associated with unfavourable prognosis. We experimentally validated that CCL2+ fibroblasts recruit myeloid cells and stimulate STAT3 activation in recruited macrophages. The development of immunosuppressive TME by CCL2+ fibroblasts were also validated in syngeneic mouse models.

GC spatial transcriptomes revealed functional cellular crosstalk involving multiple cell types among which the interaction between CCL2+ fibroblasts and STAT3-activated macrophages plays roles in establishing immune-suppressive GC TME with potential clinical relevance.

Gastric cancer (GC) is linked to high morbidity and mortality rates. Approximately two-thirds of GC patients are diagnosed at an advanced or metastatic stage. Conventional treatments for GC, including surgery, radiotherapy, and chemotherapy, offer limited prognostic improvement. Recently, immunotherapy has gained attention for its promising therapeutic effects in various tumors. Immunotherapy functions by activating and regulating the patient's immune cells to target and eliminate tumor cells, thereby reducing the tumor burden in the body. Among immunotherapies, immune checkpoint inhibitors (ICIs) are the most advanced. ICIs disrupt the inhibitory protein-small molecule (PD-L1, CTLA4, VISTA, TIM-3 and LAG3) interactions produced by immune cells, reactivating these cells to recognize and attack tumor cells. However, adverse reactions and resistance to ICIs hinder their further clinical and experimental development. Therefore, a comprehensive understanding of the advancements in ICIs for GC is crucial. This article discusses the latest developments in clinical trials of ICIs for GC and examines combination therapies involving ICIs (targeted therapy, chemotherapy, radiotherapy), alongside ongoing clinical trials. Additionally, the review investigates the tumor immune microenvironment and its role in non-responsiveness to ICIs, highlighting the function of tumor immune cells in ICI efficacy. Finally, the article explores the prospects and limitations of new immunotherapy-related technologies, such as tumor vaccines, nanotechnologies, and emerging therapeutic strategies, aiming to advance research into personalized and optimized immunotherapy for patients with locally advanced gastric cancer.

Proton pump inhibitors (PPI) have been shown to decrease the efficacy of immune checkpoint inhibitors in patients with various cancer types. However, there are few reports on their effect on patients with gastric cancer (GC). Therefore, we investigated the efficacy of nivolumab in patients with GC receiving PPI.

This retrospective study analyzed data of patients who received nivolumab monotherapy for unresectable advanced or recurrent GC at Osaka Metropolitan University Hospital between September 2017 and December 2021. The primary and secondary endpoints were progression-free survival (PFS) and overall survival (OS), respectively. PPI use was defined as within 30 days before and after initiation of nivolumab monotherapy.

Seventy-seven eligible patients were included in this analysis. PPIs were used in 33 patients, while 36 patients had a previous gastrectomy. Multivariate analysis revealed that only PPI use was an independent predictor of PFS (hazard ratio [HR] 1.93, 95% confidence interval [CI] 1.03-3.64, p = 0.042). Contrastingly, PPI use was not an independent predictor of OS.

PPIs may reduce the efficacy of nivolumab, and their use should be carefully considered in patients receiving nivolumab.

The CheckMate 649 trial demonstrated the clinical benefit of nivolumab plus chemotherapy in patients with human epidermal growth factor receptor 2 (HER2)-negative advanced gastric cancer. However, the background discrepancy between clinical practice and randomized controlled trials may impact the therapeutic strategy and prognosis of patients. This study aimed to assess the clinical significance of eligibility criteria determined by the CheckMate 649 trial and identify prognostic factors in clinical practice. A total of 160 patients with HER2-negative metastatic gastric cancer who underwent chemotherapy were retrospectively enrolled and classified into two groups based on eligibility criteria. Among the 160 patients, 76 (47.5%) and 84 (52.5%) were included in the eligible and ineligible groups, respectively. The ineligible group had a significantly lower induction of second- and third-line chemotherapy than the eligible group (P = 0.02 and P = 0.02, respectively). The median overall survival in the eligible and ineligible groups was 22.9 and 10.5 months, respectively, with the ineligible group having a significantly poorer prognosis than the eligible group (P < 0.01). Responders to first-line chemotherapy had a better prognosis than non-responders in both groups (P = 0.01 and P < 0.01, respectively). Multivariate analyses identified disease control as an independent prognostic factor in both groups (P < 0.01 and P < 0.01, respectively). Patients with a poor general condition who fulfilled the ineligibility criteria as determined using randomized controlled trials are included in clinical practice, and these criteria are related to tumor response and prognosis.

Combination therapy of chemotherapy and zolbetuximab demonstrated a significant survival benefit compared to chemotherapy alone in patients with human epidermal growth factor receptor 2 (HER2)-negative, claudin (CLDN) 18.2-positive metastatic gastric cancer (mGC). Consequently, it has been approved as a standard first-line therapy for these patients. Combination therapy of chemotherapy and immune checkpoint inhibitors (ICIs)-either nivolumab or pembrolizumab-is a standard first-line therapy for patients with HER2-negative mGCs that are positive for programmed death-ligand 1 (PD-L1) expression, as defined by a combined positive score (CPS). Although approximately 13-22% of CLDN-positive mGCs are also CPS-positive, optimal treatment for mGC patients expressing both CLDN and PD-L1 remains undetermined due to the absence of direct comparative studies between zolbetuximab and ICIs. Treatment selection under this condition has become a critical issue. In this review, we discuss the appropriate treatment selection for HER2-negative mGC patients who are double-positive for CLDN 18.2 and PD-L1 based on clinical data and differences in the mechanism of action and safety profile between zolbetuximab and ICI.

Gastric cancer remains one of the most prevalent and lethal malignancies worldwide, characterized by poor survival rates, particularly in advanced stages. In recent years, a paradigm shift in gastric cancer treatment has been witnessed with the introduction of immunotherapy and targeted therapies. This review provides a detailed examination of current immunotherapeutic strategies, including adoptive cell therapy (ACT), immune checkpoint inhibitors (ICIs), and cancer vaccines. Additionally, it explores advancements in targeted therapies, focusing on the human epidermal growth factor receptor 2 (HER2) and vascular endothelial growth factor receptor (VEGFR) signaling pathways, as well as emerging targets such as claudin 18.2. Clinical trials investigating chimeric antigen receptor T-cell (CAR-T) therapy, T-cell receptor-engineered T-cell (TCR-T) therapy, and natural killer (NK) cell-based treatments have shown promise, particularly when combined with conventional chemotherapeutic regimens. However, challenges such as cytokine release syndrome, immune-related toxicities, and scalability issues remain significant. The combination of immunotherapy with targeted therapies represents a promising approach to enhance treatment outcomes. Future directions emphasize the need to overcome resistance mechanisms and refine treatment strategies to improve efficacy while reducing adverse effects. This review aims to elucidate the current landscape of immunotherapy and targeted therapy in gastric cancer and to explore their potential in shaping the future of clinical management for this devastating disease.