From local eradication to immune priming: Paradigm shift of hyperthermic intraperitoneal chemotherapy in gastric cancer therapy

Abstract

Patients with locally advanced (pathological T4) gastric cancer remain at high risk for peritoneal recurrence despite curative surgery. Although hyperthermic intraperitoneal chemotherapy (HIPEC) reduces this risk, its inconsistent impact on overall survival has prevented its routine use. However, a recent study by Lian et al, published in World Journal of Gastroenterology, demonstrates that postoperative HIPEC improves disease-free survival and peritoneal control without severe toxicity, renewing interest. We propose a paradigm shift: The value of HIPEC lies not in cytoreduction but in its function as a potent immunogenic stimulus. By inducing immunogenic cell death, HIPEC converts residual tumor cells into an in situ vaccine. This releases tumor antigens, activates antigen-presenting cells, and catalyzes a systemic T-cell response, remodeling the tumor immune microenvironment from “cold” to “hot”. This mechanism may explain its efficacy in delaying recurrence. The variable overall survival benefit suggests that HIPEC primarily serves as an immune primer, enhancing subsequent immune-checkpoint inhibitor efficacy. Consequently, HIPEC should be redefined as a strategic immune modulator. Priority must be given to studies on synergistic “HIPEC-immune-checkpoint inhibitor” sequences and predictive biomarkers to select patients most likely to benefit. Through such strategies, HIPEC can evolve into a foundational component of immunotherapy for high-risk gastric cancer.

Key Words: Gastric cancer; Hyperthermic intraperitoneal chemotherapy; Tumor immune microenvironment; Immunogenic cell death; Immune checkpoint inhibitors

Core Tip: Postoperative hyperthermic intraperitoneal chemotherapy should be reconceptualized as an immunogenic primer that activates systemic anti-tumor immunity, rather than be viewed merely as a local cytoreductive treatment. This repositions hyperthermic intraperitoneal chemotherapy as a strategic foundation for synergistic combination with immune-checkpoint inhibitors. Consequently, future research should prioritize the definition of optimal synergistic sequences and the identification of predictive biomarkers to pave the way for this precision immunotherapy strategy.

This editorial refers to "Efficacy and safety of sequential hyperthermic intraperitoneal chemotherapy following surgery for pathological T staging 4 gastric cancer" by Lian et al, 2026; https://doi.org/10.3748/wjg.v32.i6.115556.

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INTRODUCTION

Gastric cancer (GC) ranks as the fifth most common malignancy and the fourth leading cause of cancer-related death worldwide, posing a significant and ongoing challenge in clinical oncology[1]. Despite advances in the multidisciplinary treatment model centered on surgery, the prognosis for patients with locally advanced disease, particularly pathological T4 (pT4) stage, remains unfavorable. The pT4 stage indicates tumor penetration through the serosal layer or invasion into adjacent organs. In this setting, tumor cells readily shed and implant within the peritoneal cavity, forming metastatic deposits. This process leads to most postoperative fatal recurrences[2]. Peritoneal metastasis drives the poor prognosis in GC, resulting in a five-year survival rate of only about 6% and serving as the leading cause of death[3]. Consequently, effectively preventing peritoneal metastasis has emerged as a central issue in improving outcomes for this high-risk patient population.

Against this backdrop, hyperthermic intraperitoneal chemotherapy (HIPEC) has been developed. Its fundamental principle involves the continuous circulation of a warmed chemotherapeutic perfusate (typically approximately 43 °C) within the abdominal cavity, which harnesses three primary mechanisms of action: Hyperthermia, regional chemotherapy, and mechanical lavage. In recent years, HIPEC has been extensively explored for the prevention and treatment of peritoneal metastasis in GC. Numerous studies have demonstrated that cytoreductive surgery combined with HIPEC can prolong survival in patients with established peritoneal metastases[4,5]. However, the value of prophylactic HIPEC for locally advanced GC patients without visible peritoneal metastasis remains controversial. While some studies confirm that prophylactic HIPEC improves disease-free survival (DFS) and reduces the rate of peritoneal metastasis[2,6], other randomized controlled trials (RCTs) and meta-analyses have reported negative findings[7,8]. This consistent DFS benefit coupled with contradictory overall survival (OS) outcomes suggests the need to look beyond HIPEC as a mere “local eradication” technique and explore its deeper anti-tumor mechanisms.

In this context, the retrospective study led by Lian et al[9], published in this issue of the World Journal of Gastroenterology, provides crucial evidence prompting a re-evaluation of HIPEC’s value. This study robustly demonstrates that early postoperative HIPEC (performed within 1-5 days following surgery) combined with adjuvant chemotherapy significantly prolongs DFS and reduces the incidence of peritoneal metastasis compared to adjuvant chemotherapy alone, with a comparable safety profile. Using this study as a springboard, this article aims to challenge the conventional view of HIPEC. We will analyze the potential role of HIPEC in reshaping the therapeutic paradigm for GC from the forefront of tumor immunology and outline future directions for the field. This perspective article aims to synthesize recent clinical and preclinical evidence to propose and discuss this paradigm shift, outlining its implications for future research and clinical trial design.

CURRENT LANDSCAPE: THE EVIDENCE BASE AND CENTRAL PARADOX OF HIPEC IN GC TREATMENT

The role of HIPEC in the multidisciplinary management of locally advanced GC has been debated for over two decades, resulting in a complex and sometimes contradictory evidence base. On the one hand, support for its efficacy comes from various retrospective studies and meta-analyses[4,10-12]. On the other hand, several rigorously designed RCTs have reported ambiguous or even negative findings[7,8]. This pattern of “retrospective support vs prospective skepticism” is the main reason hindering its routine clinical adoption.

Evidence supporting the effectiveness of HIPEC is primarily derived from retrospective studies[10-12] and meta-analysis[4]. These studies consistently show that adding HIPEC to radical surgery significantly reduces postoperative peritoneal recurrence risk and improves DFS. The latest study by Lian et al[9], published in World Journal of Gastroenterology, provides strong reinforcement within this body of evidence. Their data demonstrate that postoperative HIPEC (administered early after surgery) combined with adjuvant chemotherapy significantly increases the 3-year DFS rate and substantially lowers the incidence of peritoneal metastasis compared to adjuvant chemotherapy alone, with a comparable safety profile.

Challenging this perspective is evidence from a few high-quality RCTs, particularly those evaluating the “prophylactic” role of HIPEC. Among these, two randomized studies[7,8] reported that HIPEC did not significantly improve OS. These negative results have sparked extensive academic debate and led to cautious recommendations regarding prophylactic HIPEC in many clinical guidelines.

Several key factors may explain this seemingly contradictory evidence. First is the heterogeneity of study populations. RCTs often enroll all GC patients undergoing radical surgery, not exclusively those at the highest risk of peritoneal metastasis, such as patients with pathologically confirmed pT4 stage. This likely dilutes the measurable “preventive” effect of HIPEC. In contrast, many retrospective studies specifically focus on this high-risk pT4 population, thereby more clearly demonstrating its potential value[13,14]. Second, variations exist in HIPEC technical parameters and timing. Differences across studies in drug selection, perfusion temperature, duration, and administration timing (intraoperative vs postoperative) may directly impact outcomes[13,14]. Third, and most crucially, is the choice of study endpoint. Nearly all studies, including the negative RCTs, observed a consistent and significant DFS benefit with HIPEC. This reveals a critical fact: HIPEC is effective in controlling local disease and delaying recurrence. However, OS is a composite endpoint influenced by numerous subsequent factors; for instance, effective later-line therapies received after recurrence may compensate for the loss in OS, thereby obscuring a more pronounced survival benefit attributable to HIPEC[13]. A pertinent example is the potential use of immune-checkpoint inhibitors (ICIs) upon metastatic relapse. When HIPEC primes the immune system, these patients may particularly benefit from subsequent treatment with ICIs, potentially attenuating the OS difference between groups in a trial not designed to assess the efficacy of this combination. This logic directly reinforces the concept of HIPEC serving as an immune primer to enhance the efficacy of subsequent ICIs.

It is also important to acknowledge non-immunological factors that may contribute to the observed OS dilution. These factors include the heterogeneity of postoperative systemic treatments, where effective salvage regimens upon recurrence can mitigate survival differences between study arms. Additionally, trial design elements, such as crossover (where patients in the control group receive HIPEC upon progression) or competing risks of death, can undermine the true OS benefit attributable to the initial intervention. These factors collectively suggest that the DFS-OS paradox is multifactorial, and the immunological hypothesis presented here represents a compelling, but not exclusive, explanatory layer.

Nevertheless, recent well-conducted studies have established a significant OS advantage for HIPEC in specific contexts. For instance, cytoreductive surgery plus HIPEC provided a marked survival benefit over systemic chemotherapy alone for patients with peritoneal metastases in a large national database analysis[15]. Similarly, integrating HIPEC into neoadjuvant or adjuvant regimens has been shown to not only reduce peritoneal recurrence but also improve OS in high-risk localized disease[16,17]. This underscores that when applied to appropriately selected populations within optimized strategies, HIPEC can confer a definitive survival advantage.

In summary, the current evidence suggests that HIPEC has a definitive effect on its primary goal of preventing peritoneal metastasis when applied to high-risk populations, such as pT4 stage patients. This point has been repeatedly validated across multiple studies, including the recent work by Lian et al[9]. The apparent contradiction with RCTs regarding OS benefit stems more from differences in study design, patient selection, and endpoint assessment rather than a complete negation of its efficacy. To visually synthesize this complex and contradictory evidence, a summary of key studies is presented in Table 1[4,6,7,9,10,17]. Understanding this allows us to move beyond the simplistic “OS-centric” framework and explore the deeper value of HIPEC, which extends beyond mere local control.

Table 1 Summary of key evidence on hyperthermic intraperitoneal chemotherapy for locally advanced gastric cancer.

Ref.	Population and design	DFS outcome	OS outcome	Key findings and interpretation
Pivotal recent evidence
Lian et al[9], 2026	The pT4 stage, non-metastatic. Retrospective cohort study	Significantly improved (higher 3-year DFS rate)	Favorable trend (not significant)	Provides key evidence that postoperative HIPEC reduces peritoneal recurrence and improves DFS, forming the basis for re-evaluating its role as an immune primer
Supportive evidence: Retrospective studies
Reutovich et al[10], 2019	Serosa-invasive (pT4), non-metastatic. Retrospective study	Significantly improved	Improved	Demonstrates that HIPEC reduces peritoneal recurrence and improves survival in a high-risk cohort, supporting precision application
Liu et al[6], 2023	Locally advanced GC. Propensity score-matched analysis	Significantly improved (HR = 0.592; P = 0.042)	Trend toward improvement	Confirms that prophylactic HIPEC reduces peritoneal recurrence risk and improves DFS in clinical T4 patients
Supportive evidence: Meta-analysis
Granieri et al[4], 2021	GC (mixed stages). Meta-analysis of RCTs	Significant benefit	Potential benefit/requires confirmation	Pooled data supports a consistent DFS advantage. OS benefit appears contingent on patient selection (e.g., high-risk features)
Evidence illustrating the “central paradox”
Fan et al[7], 2021	Locally advanced GC (M0). Phase II RCT	Improved (primary endpoint met)	No significant difference	Epitomizes the central paradox: A clear, protocol-defined DFS benefit did not translate into an OS advantage, highlighting complexities in endpoint interpretation and subsequent therapies
Gong et al[17], 2024	Locally advanced GC. Retrospective (propensity score matching) study	Significantly improved (HR = 0.569; P = 0.013)	No significant difference	Reinforces the paradox pattern: Significant reduction in isolated peritoneal metastasis and DFS improvement, yet no OS benefit, underscoring the need for combination strategies (e.g., with immunotherapy)

It synthesizes the primary clinical evidence regarding hyperthermic intraperitoneal chemotherapy for locally advanced gastric cancer, highlighting the consistent pattern of improved disease-free survival and reduced peritoneal recurrence, particularly in high-risk populations (e.g., pathological T4 stage). The contrasting overall survival outcomes between supportive retrospective studies and randomized trials epitomize the “central paradox” in the field, which forms the rationale for re-evaluating hyperthermic intraperitoneal chemotherapy’s mechanism beyond local cytotoxicity and toward systemic immune modulation. DFS: Disease-free survival; GC: Gastric cancer; HIPEC: Hyperthermic intraperitoneal chemotherapy; HR: Hazard ratio; OS: Overall survival; pT4: Pathological T4; RCT: Randomized controlled trial.

THE ESSENTIAL QUESTION: A PARADIGM SHIFT FROM LOCAL CYTOTOXICITY TO SYSTEMIC IMMUNE MODULATION

The understanding of HIPEC’s value stands at a critical crossroads. The traditional view frames it as an efficient “local cytotoxic” therapy aimed at the physical and chemical eradication of residual tumor cells within the peritoneal cavity. However, the key finding from Lian et al’s study[9] – a significant DFS improvement without a statistically significant OS benefit – when viewed within a broader theoretical framework, suggests a more explanatory paradigm. We hypothesize that the true potential of HIPEC may lie in its capacity to “mobilize” and “reshape” the immune system to fight cancer, acting as a systemic organizer. This perspective provides a plausible mechanistic explanation for the observed clinical pattern. Recent research indicates that HIPEC’s effects extend far beyond simple “local cytotoxicity”, involving a complex molecular regulatory network that modulates cell survival signaling pathways (e.g., STAT3, AKT, ERK), influences oxidative stress and antioxidant systems, suppresses chemotherapy resistance-related protein expression, and regulates programmed death ligand-1 (PD-L1) expression[18]. This conceptual shift from “local cytotoxicity” to “systemic immune modulation” is essential for understanding its future value.

Given the physiological blood-peritoneal barrier, a key question regarding systemic immune modulation is how intraperitoneal events affect the systemic immune response. While the blood-peritoneal barrier limits passive diffusion of large molecules, the immunogenic cascade initiated by HIPEC is primarily mediated by the active trafficking of immune cells. Antigen-presenting cells (APCs), such as dendritic cells, that capture tumor antigens in the peritoneal cavity can migrate via lymphatic vessels to regional lymph nodes, where they prime naive T cells. These activated, tumor-specific T cells then enter the systemic circulation and can return to tumor sites[19]. Furthermore, hyperthermia may transiently increase vascular permeability and modulate lymphatic flow, potentially facilitating the migration of immune cells[19]. Therefore, the systemic immunological effects of HIPEC likely rely on this cellular “relay” mechanism rather than the systemic dissemination of intraperitoneal cytokines or antigens.

First, the mechanisms of action underlying HIPEC hold profound immunological implications. Hyperthermia is not merely a physical ablative force. Modern immunology demonstrates that specific thermal stress can induce “immunogenic cell death (ICD)” in cancer cells[20]. During ICD, released “danger signals” such as calreticulin, adenosine triphosphate, and high mobility group box 1 are recognized by APCs, such as dendritic cells, thereby initiating a tumor-specific T-cell-mediated immune response[20]. Consequently, the hyperthermia component in HIPEC transcends its role as a physical killing tool, instead functioning as a means to generate an “endogenous vaccine”. Chemotherapeutic agents used in HIPEC (e.g., cisplatin, mitomycin, docetaxel, 5-fluorouracil) not only exert direct cytotoxicity but also possess immunomodulatory functions. They can induce ICD and inhibit the activity of immunosuppressive cells such as regulatory T cells[21,22]. Certain agents (e.g., oxaliplatin) can also promote dendritic cell maturation and function, enhancing their antigen-presenting capacity[21]. In the context of HIPEC, chemotherapy and hyperthermia act synergistically to induce a more robust ICD[23,24]. The superior DFS observed in the HIPEC group in Lian et al’s study[9] may therefore stem not solely from the pharmacokinetic advantage of high local drug concentrations, but potentially from the synergy between the chemotherapeutic agent (e.g., docetaxel or 5-fluorouracil) and heat, which induces stronger and broader ICD, thereby eliciting more durable anti-tumor immunological memory. Furthermore, the mechanical lavage ensures uniform distribution of the chemotherapeutic agent throughout the abdominal cavity, maximizing the distribution and efficacy of both cytotoxic and immunomodulatory effects.

Second, this new perspective of HIPEC as an “immunogenic primer” provides a coherent explanation for the central paradox in the clinical evidence. The consistent DFS improvement across nearly all studies serves as powerful evidence for its role as an immunogenic stimulus[4,10-12,25]. By inducing ICD and activating APCs, HIPEC establishes an “active immune” state against the tumor. This immune memory can effectively clear or suppress postoperative micrometastatic disease, thereby significantly delaying recurrence and prolonging DFS[23,24]. The variable OS benefit, however, suggests that even if HIPEC initiates an immune response, the tumor microenvironment may subsequently re-establish an immunosuppressive state through mechanisms like upregulation of immune checkpoint molecules (e.g., PD-L1) and T-cell exhaustion, leading to a “waning” of the initial response[26]. OS is a more complex endpoint influenced by multiple factors. On one hand, the immune system possesses memory; thus, in theory, this HIPEC-primed anti-tumor immunity should translate into long-term survival benefits[27]. On the other hand, tumor cells exhibit high heterogeneity and immune evasion capabilities. Over time, even after an initial HIPEC-induced immune response, the tumor microenvironment (TME) can regain an immunosuppressive state through upregulated PD-L1/programmed death 1 signaling and T-cell exhaustion[26,28]. Additionally, individual patient factors, such as baseline immune status and tumor molecular subtype, significantly influence the strength and durability of the immune response[29]. Therefore, the failure to demonstrate an OS benefit in some trials may not indicate that HIPEC failed to prime immunity, but rather that this primed response was insufficiently potent or durable to effectively counter subsequent tumor progression. This also explains why the OS curve in Lian et al’s study[9] showed a favorable trend without reaching statistical significance, a likely consequence of the limited sample size typical of a phase II trial.

Thus, the essential question has evolved from “can HIPEC kill cancer cells” to “can HIPEC effectively and durably activate anti-tumor immunity”. The study by Lian et al[9], with its robust DFS benefit, provides strong clinical support for HIPEC’s capacity to activate anti-tumor immunity. The future of HIPEC should not be as an optional procedural adjunct between surgery and systemic chemotherapy. Instead, it should be repositioned as a crucial “immune primer” and “sensitizer” within the comprehensive treatment strategy. Its role can be likened to that of a “therapeutic vaccine”, whose value lies in mobilizing the patient’s own immune system to perform the long-term surveillance and clearance tasks that surgery and pharmacotherapy alone cannot achieve.

INNOVATIVE DIRECTION: ESTABLISHING A “HIPEC-IMMUNE CHECKPOINT INHIBITOR” SYNERGISTIC THERAPEUTIC PARADIGM

Building upon the reconceptualization of HIPEC as an immunogenic primer, a strategic combination of HIPEC with ICIs represents a highly promising and innovative direction and a novel synergistic therapeutic paradigm. The core logic is to utilize HIPEC as a “pioneer” intervention to break tumor immune silence, converting an immunologically “cold” TME into a “hot” one, thereby paving the way for subsequent ICIs, which act as the “main force”, to exert enhanced efficacy, achieving a synergistic sensitization effect.

Understanding this synergy hinges on recognizing the limitations of ICIs and HIPEC’s potential to overcome them. ICIs function by blocking inhibitory signals on T cells, effectively “releasing the brakes”. However, their efficacy is constrained by the state of the TME. In an immunologically “cold” tumor microenvironment, characterized by a lack of infiltrating effector T cells, ICIs often prove ineffective[30,31]. HIPEC directly addresses this challenge. By inducing ICD, HIPEC releases a large pool of tumor antigens and activates APCs. This initiates a robust, tumor-specific T-cell response, promoting the infiltration of effector T cells into the tumor site and transforming a “cold” TME into an immunologically “hot” one[18,32]. Within such a pre-activated, T-cell-rich microenvironment, the efficacy of ICI can be significantly amplified. Therefore, the combination of HIPEC and ICIs represents an ideal sequential strategy termed “priming and releasing”.

The work of Lian et al[9] provides direct clinical-translational support for this paradigm. Their adopted “postoperative sequential” HIPEC protocol was safe and feasible. By clearing residual disease and initiating anti-tumor immunity during a window of relatively low tumor burden, it created ideal conditions for the subsequent administration of systemic therapies, including ICIs. A reasonable hypothesis is that combining ICIs on this HIPEC-primed immune foundation would not only improve DFS but also potentially amplify the OS benefit.

This new paradigm is also grounded in a solid research foundation. Preclinical studies have confirmed that hyperthermia can upregulate PD-L1 expression on tumor cells[18]. At the clinical level, strategies combining locoregional therapies with ICIs have shown promise[33]. Given its greater immunogenic potential compared to conventional chemotherapy, HIPEC combined with ICIs holds particular promise. The DRAGON-01 trial demonstrated that intraperitoneal combination therapy (paclitaxel) plus systemic chemotherapy significantly improved OS compared to systemic chemotherapy alone in GC patients with peritoneal metastases[34]. This result indirectly supports the notion that delivering potent immunostimulatory or chemotherapeutic agents directly into the peritoneal compartment can yield benefits surpassing those of systemic treatment alone.

In conclusion, the “HIPEC-ICI” synergistic therapeutic paradigm represents a promising direction derived from existing evidence and theoretical reasoning. This perspective elevates HIPEC from a mere local control modality to a foundational component of systemic immunotherapy.

Despite its promise, translating this paradigm into practice must navigate several challenges. It is crucial to emphasize that this synergistic paradigm remains speculative and requires rigorous clinical validation. There are substantial challenges for its clinical translation, including: (1) Toxicities and safety issues: Potential overlapping or synergistic toxicities require careful consideration. HIPEC can induce a systemic inflammatory response and local tissue irritation, while ICIs can lead to immune-related adverse events (irAEs) affecting various organs. A key theoretical concern is whether the pro-inflammatory microenvironment established by HIPEC can lower the threshold for irAEs or exacerbate the severity of irAEs, particularly gastrointestinal or hepatic events. Future clinical trials must incorporate robust, proactive monitoring and management protocols for irAEs. They may need to explore modified ICI dosing or sequencing to optimize the safety profile of their combinations; (2) Optimal sequencing and timing: The ideal treatment sequence (e.g., neoadjuvant HIPEC followed by adjuvant ICI vs concurrent or a “sandwich” approach) remains to be defined and likely relies on tumor stage and biology and the specific agents used. The goal is to leverage HIPEC-induced immune activation to maximize the effects of ICIs; (3) Cost-effectiveness and accessibility: The combined regimen’s significant resource intensity necessitates formal health economic assessments to justify its broader adoption. Furthermore, standardization of HIPEC protocols and improved access to this specialized procedure are prerequisites for the widespread implementation of the combination strategy; and (4) Risk-benefit assessment in prophylactic settings: Any discussion regarding the prophylactic use of HIPEC must be tempered by a true assessment of procedural risks. One analysis reported a complication rate of 60.5% for cytoreductive surgery plus HIPEC compared to 27.9% for gastrectomy alone (P < 0.001), effectively doubling the risk[35]. The incidence of grade ≥ 3 complications[3], such as prolonged hospitalization, abdominal infection, anastomotic leak, adhesive small-bowel obstruction, delayed gastric emptying, and bone marrow suppression[3,35], was reported to be nearly 17%. Therefore, the established and significant absolute improvement in 3-year DFS offered by prophylactic HIPEC[36] comes with a quantifiable increase in serious morbidity. Consequently, the decision to employ HIPEC must be individualized, with the definitive survival advantage weighed carefully against the potential for added procedural risk in the context of shared decision-making. Addressing these challenges will require well-designed prospective studies incorporating comprehensive toxicity profiling, biomarker-guided patient selection, and adaptive trial designs to efficiently identify the most beneficial combinations and sequences.

Future clinical research should leverage this insight to systematically explore the optimal timing, dosing, and patient selection for this combination, ultimately aiming to define the best individualized treatment strategy for high-risk patients.

TRANSLATING THE VISION INTO PRACTICE: A PATH TOWARD A PRECISE AND PATIENT-CENTERED FUTURE

Translating the hypothetical “HIPEC-Immunotherapy” synergistic paradigm from a theoretical blueprint into clinical practice requires a clear, actionable pathway to benefit patients. The core research endeavor is to advance the application of HIPEC from its current, often empirical and ambiguous use to a new stage of “precision and individualization” guided by biomarkers. This transition is crucial not only for maximizing therapeutic efficacy but also for facilitating its broader acceptance and integration into standard treatment protocols. The proposed multi-step pathway, encompassing integration into multidisciplinary care, biomarker development, and innovative trial design, is schematically overviewed in Figure 1.

Figure 1 A roadmap for personalized decision-making in high-risk gastric cancer (e.g., pathological T4 stage). This flowchart delineates a multi-path intervention framework for high-risk gastric cancer patients, anchored in multidisciplinary team evaluation and biomarker-guided stratification. It encompasses therapeutic strategies across neoadjuvant, conversion, and adjuvant settings, proposes validation through optimized clinical trials (umbrella/platform trials), and ultimately aims to guide personalized treatment strategies to improve long-term patient outcomes. In the diagram, solid arrows indicate the core clinical decision pathway, while dashed arrows denote associated research directions. Different node shapes are used for clarity: Rectangles represent core clinical/decision points, ovals signify associated research modules, and the diamond denotes the final outcome metric. CT: Chemotherapy; HIPEC: Hyperthermic intraperitoneal chemotherapy; ICI: Immune-checkpoint inhibitor; pT4: Pathological T4.

The primary task is to define the precise role of HIPEC within the multidisciplinary team for GC. HIPEC should be organically integrated into the multidisciplinary team workflow centered on surgery. Its potential strategic positions include: (1) In the neoadjuvant setting, combining with chemotherapy to downstage tumors and improve R0 resection rates; (2) In the conversion therapy setting, serving as part of a strategy for initially unresectable disease; and (3) In the adjuvant setting (the focus of Lian et al’s work[9]), acting as a critical intervention to eradicate micrometastatic disease and prevent recurrence, potentially in combination with adjuvant immunotherapy. In the adjuvant setting, the timing of HIPEC requires careful consideration. The strategy employed by Lian et al[9], early postoperative HIPEC based on the final pT4 pathology, ensures accurate patient selection but entails a separate procedure. As an alternative, risk-adapted intra-operative strategy, based on suspected serosal involvement (using frozen section, pre-operative imaging, or laparoscopic assessment), can resolve the need for a second intervention but increases the risk of overtreatment, ultimately down-staged by final pathology. Developing and validating prospective selection tools, such as quantitative computed tomography serosal scoring and molecular examination of the peritoneal lavage, is needed to identify high-risk patients before or during surgery, thereby refining the decision-making framework and moving beyond reliance on the postoperative pT4 label alone.

Building upon this, the next imperative is to construct and validate a biomarker system for “precision selection” to predict HIPEC efficacy. This is the cornerstone of achieving individualization. Future research should prioritize discovering and validating biomarkers across several key categories to enable precision selection. These include: (1) Tumor immune microenvironment markers, such as baseline tumor-infiltrating lymphocyte status, which has shown prognostic value in related contexts and may predict response to immunotherapies[37]; (2) Intrinsic tumor cell features, like specific gene expression profiles associated with treatment sensitivity, such as signatures related to DNA damage repair or oncogenic pathways[38]; (3) Dynamic monitoring of circulating tumor DNA for real-time response assessment, as the clearance of circulating tumor DNA post-treatment has been correlated with improved outcomes in other cancers and could serve as a rapid indicator of HIPEC efficacy[39]; and (4) Predictive serum biomarker panels, including multi-analyte protein signatures that have shown promise in predicting immunotherapy benefit in other malignancies[40]. Together, these tools will form a decision-making framework to guide HIPEC application.

The ultimate objective is to prospectively validate the new paradigm through optimized clinical trial designs. Future trials must adopt more complex, strategy-exploring designs. For example, an umbrella trial could be designed where postoperative pT4 stage patients are stratified based on molecular features (e.g., microsatellite instability status, human epidermal growth factor receptor 2 expression, tumor mutational burden). Different strata would then explore the efficacy of various regimens, such as “standard adjuvant therapy”, “standard therapy plus HIPEC”, and “standard therapy plus HIPEC plus ICIs”. This approach directly addresses the critical question of “which patient benefits most from which regimen”. Additionally, platform trial models offer an efficient framework for evaluating multiple HIPEC-based combination strategies (e.g., with different ICIs).

In summary, the path to precision is clear: It must be anchored in multidisciplinary care, guided by biomarkers, and validated through optimized trials. By precisely applying HIPEC to patients most likely to benefit and rationally combining it with other therapies, this approach holds the promise to unlock its full potential – transforming pT4 GC from a late-stage disease with a poor prognosis into a controllable, treatable chronic condition, thereby genuinely extending patient lives and improving their quality of life.

CONCLUSION

Based on the latest evidence from Lian et al[9], we propose a novel hypothesis that the fundamental value of HIPEC in treating pT4 GC may reside in its role as an immune primer, rather than in local control alone. By inducing ICD, HIPEC converts residual tumor cells into an “endogenous vaccine”, thereby explaining its consistent DFS benefit. Looking ahead, establishing a “HIPEC-immune checkpoint inhibitor” synergistic paradigm represents a pivotal direction for enhancing efficacy. Realizing this vision requires a concerted research effort focused on biomarker discovery to advance treatment toward precision and individualization, with the ultimate aim of establishing HIPEC as a strategic pillar for improving long-term outcomes in high-risk GC patients.