In the 21st century, gastric cancer remains a major global health threat, ranking as the fourth leading cause of cancer-related mortality (7.7%), following lung (18%), colorectal (9.4%), and liver cancers (8.3%) (1). Over the past half-century, declining Helicobacter pylori prevalence and improved food preservation have significantly reduced the incidence and mortality of non-cardia gastric cancer (2). However, the incidence of gastroesophageal junction (GEJ) cancer has risen in some countries. Although R0 resection rates for GEJ cancer are comparable to those for non-cardia gastric cancer, systemic recurrence rates are significantly higher (*p* = 0.031), and median survival is markedly shorter (26 months vs. 69 months; *p* < 0.001) (3).

Surgical resection remains the primary curative approach for gastric cancer and the most effective method to prolong patient survival (4). In operable gastric or lower esophageal adenocarcinoma, neoadjuvant chemotherapy reduces tumor size and stage, significantly increases R0 resection rates, and improves progression-free survival and overall survival (5). In recent years, immune checkpoint inhibitors targeting cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4), programmed death (PD)-1, and PD-ligand 1 (PD-L1) have demonstrated durable responses in subsets of patients with metastatic disease (6). With the expanding use of PD-1/PD-L1 inhibitors in clinical practice (7, 8), emerging evidence suggests that combination therapies incorporating anti-PD-1 agents may represent the future of cancer immunotherapy (9, 10). This study aims to consolidate evidence for neoadjuvant PD-1 inhibitor therapy in gastric cancer and propose strategies for optimizing treatment regimens in G/GEJ tumors.

This systematic review and meta-analysis were conducted and reported in accordance with the PRISMA guidelines. The study protocol was registered on PROSPERO (Registration ID: CRD42024619916).

The initial search identified 1,773 studies. After removing 473 duplicates, 1,300 studies underwent title and abstract screening, excluding 1,249 articles. Full-text review of the remaining 63 studies led to the inclusion of 12 articles that met the eligibility criteria for this meta-analysis.

Among the 12 studies, 9 were single-arm trials and 3 were retrospective studies. The primary PD-1/PD-L1 inhibitors evaluated included tislelizumab, camrelizumab, durvalumab, atezolizumab, sintilimab, and pembrolizumab. Detailed study characteristics are summarized in Table 1, and the search flowchart is shown in Figure 1. The pooled cohort comprised 428 patients, with 406 undergoing surgical intervention. Of these, 378 patients (93.1%) achieved R0 resection.

Over the past decades, therapeutic advancements in gastric cancer (GC) have expanded treatment options, including perioperative chemotherapy and adjuvant chemoradiotherapy, which reduce recurrence risks and improve survival. Immune checkpoint inhibitors (ICIs) and targeted therapies are now incorporated into clinical guidelines globally. For instance, HER2-targeted therapies have improved objective response rates (ORR: 47.3% vs. 34.5%) and progression-free survival (PFS: 6.7 vs. 5.5 months; HR: 0.71, 95% CI: 0.59–0.85; *p* < 0.0002) (19). ICIs, particularly PD-1/PD-L1 inhibitors, have shown promise in untreated advanced or metastatic GC patients with high microsatellite instability (MSI-H) or mismatch repair deficiency (dMMR) (20), offering new hope for unresectable cases. Unlike conventional therapies, immunotherapy exerts antitumor effects by activating the host immune system and reversing immune suppression. Emerging evidence suggests that immunotherapy can potentiate T-cell responses against tumor antigens while enhancing the detection and elimination of micrometastatic deposits beyond the resected tumor margins. When combined with chemotherapeutic agents (e.g., paclitaxel, platinum compounds), it may induce immunogenic cell death (ICD), triggering the release of damage-associated molecular patterns (DAMPs) that enhance antigen presentation by APCs. This mechanism synergizes with PD-1/PD-L1 inhibitors to achieve superior therapeutic efficacy. Notably, PD-1 inhibitors are now approved for unresectable/metastatic GC in several countries, despite incomplete mechanistic understanding (21).

Treatment efficacy: The pooled pCR rate of 21.5% [0.162; 0.271] observed in this meta-analysis exceeds the 14.3% pCR reported in the POET trial for esophagogastric adenocarcinoma and approaches the 23% rate in the CROSS study (22). Notably, Verschoor YL 2024 achieved a pCR of 45%. The mean MPR rate was 56.3% [0.475; 0.649], with 3 studies reporting MPR > 60%, including a remarkable 70% in Verschoor YL 2024.

Safety profile: The pooled R0 resection rate of 95.2% [95% CI: 0.896; 0.989] surpasses rates from RESONANCE (73.1%) (19, 20), CROSS (82–85%) (22), and FLOT4-AIO (84%) (23), suggesting enhanced tolerability of PD-1/PD-L1 inhibitor-based neoadjuvant regimens.

Limitations: Furthermore, this study has several limitations. First, the analyzed endpoints were short-term. Moreover, due to a lack of reported data in the included studies, critical long-term outcomes such as overall survival (OS), disease-free survival (DFS), and the incidence of adverse immune reactions were not assessable in this analysis. This omission may introduce bias regarding the long-term survival impact of this treatment regimen. Second, the overall sample size was limited, comprising only 428 patients (406 underwent surgical intervention), with merely 88 patients achieving a pathological complete response (pCR). This small sample size, particularly the low number of pCR events, results in limited statistical power. It is important to note that treatment efficacy varies significantly across different tumor types. Unfortunately, the studies included in our analysis lacked sufficient data to perform further subgroup analyses based on tumor type. Additionally, since most of the included studies were single-arm trials without control groups, residual confounding factors may have led to an overestimation of the treatment effect. Furthermore, the risk of funnel plot asymmetry is heightened due to potential publication bias, as single-arm studies with positive results are more likely to be published, while long-term negative outcomes may remain unreported.

Future directions: Additionally, while the study results demonstrated encouraging outcomes for R0 resection rates with neoadjuvant PD-1/PD-L1 inhibitor therapy, the analysis was limited by the absence of high-quality randomized controlled trials (RCTs). Among the 12 included studies, 9 were single-arm trials and 3 were retrospective analyses. Single-arm trials cannot exclude time effects or selection bias, making it difficult to establish causal relationships. Furthermore, substantial heterogeneity existed in treatment protocols: the specific PD-1/PD-L1 inhibitors used, chemotherapy regimens, and treatment cycles were not standardized. The included patients also encompassed varying disease stages. This variability complicates the interpretation of whether these factors influenced treatment efficacy or safety. Concurrently, the lack of standardized biomarker testing and stratified study designs within the included literature represents a missed opportunity for identifying predictive biomarkers of response. Therefore, future research should focus on determining optimal neoadjuvant PD-1/PD-L1 inhibitor-based regimens to maximize rates of pathological complete response (pCR) and overall survival (OS). Key priorities include defining the optimal treatment duration and timing of surgery, and incorporating biomarker stratification (e.g., PD-L1 Combined Positive Score (CPS), Microsatellite Instability (MSI) status). The integration of biomarker-driven patient stratification will be pivotal in future clinical practice, offering significant improvements in objective response rates (ORR) and survival outcomes while minimizing ineffective treatments and associated toxicities. For example, PD-L1-negative patients, who typically exhibit response rates below 10%, could avoid unnecessary immunotherapy, thereby reducing financial burdens and the risk of immune-related adverse events (irAEs). Conversely, MSI-H patients may derive greater benefit from immunotherapy alone or de-escalated regimens, circumventing the overt use of chemotherapy (24, 25). Prospective trials should incorporate predictive biomarker analyses to validate potential signatures.