Locally advanced gastric cancer (LAGC) remains a major global health burden (1), and neoadjuvant/perioperative therapy has been widely adopted to improve resectability and long-term outcomes (2–4). However, the choice of the optimal chemotherapy backbone continues to be a pivotal clinical decision, as it directly affects treatment intensity, tolerability, perioperative safety, and the likelihood of achieving meaningful pathological response. In Western practice, 5-FU+oxaliplatin+Docetaxel+Leucovorin (FLOT) is commonly used as the perioperative standard (5, 6), whereas S-1+oxaliplatin (SOX) is frequently preferred in East Asia owing to its convenience and established efficacy in Asian populations (7–9). The phase II DRAGON III trial recently provided direct evidence that neoadjuvant FLOT and SOX may yield comparable efficacy and safety, supporting both regimens as acceptable backbones in resectable LAGC (10, 11).

With accumulating evidence supporting the addition of PD-1 inhibitors to perioperative chemotherapy, neoadjuvant immunochemotherapy has rapidly entered routine clinical practice. Nevertheless, the optimal chemotherapy partner for PD-1 blockade remains undefined (12–14). Although FLOT and SOX are among the most widely used and guideline-endorsed regimens, head-to-head data comparing PD-1 inhibitor plus FLOT versus PD-1 inhibitor plus SOX remain lacking. Therefore, we conducted a real-world comparative cohort study to evaluate the efficacy and safety of neoadjuvant PD-1 inhibitor combined with SOX versus FLOT in patients with resectable LAGC, and to explore prognostic factors associated with survival.

This single-center, real-world retrospective cohort study compared the efficacy and safety of neoadjuvant PD-1 inhibitor plus SOX versus PD-1 inhibitor plus FLOT in patients with locally advanced G/EGJ adenocarcinoma. Our results demonstrated that PD-1 inhibitor combined with either FLOT or SOX achieved comparable long-term outcomes (OS and RFS), pathological responses (pCR and MPR), and overall safety profiles. Additionally, PD-1 inhibitor plus SOX was associated with shorter operative time and lower intraoperative blood loss compared with PD-1 inhibitor plus FLOT.

Substantial geographic differences have long existed in the selection of perioperative chemotherapy backbones: FLOT is more commonly adopted (5, 6) in Western practice and has also been reported in China (17), whereas SOX is widely used across East Asia (9, 18). The DRAGON III trial directly compared FLOT and SOX and suggested broadly similar efficacy and safety in the neoadjuvant chemotherapy setting (10, 11). With immunotherapy emerging as a major perioperative strategy, numerous studies on perioperative immunotherapy combined with chemotherapy for gastric cancer have been conducted. The DANTE (IKF-s633) and NEOSUMMIT-01 trails have shown that immunotherapy combined with chemotherapy can significantly increase the pathological response rate (12, 14). The KEYNOTE-585 and MATTERHORN trials further demonstrated the benefits of immunochemotherapy on survival outcomes (19, 20), direct evidence remains limited regarding which chemotherapy backbone is optimal for combination with PD-1 blockade. In routine clinical practice, our comparative evaluation demonstrated similar ORR and DCR between the two regimens, with no significant differences in pCR or MPR. Survival analyses further indicated no statistically significant differences in OS and RFS, suggesting that, in this cohort, the overall clinical benefit achieved by combining PD-1 inhibitors with either backbone was comparable. From a real-world perspective, these findings support the notion that both SOX and FLOT can serve as feasible “platform” regimens for perioperative immunochemotherapy in East Asian populations, and regimen selection may be individualized based on tolerability, treatment convenience, and institutional perioperative management experience. Notably, recent phase III trials have reinforced the role of perioperative immunochemotherapy: KEYNOTE-585 demonstrated improvement in event-free survival (EFS) (19), and MATTERHORN reported that adding immunotherapy to a FLOT backbone further significantly improved EFS and OS (20). In this context, our prognostic analyses are clinically informative. Cox regression showed that MPR was independently associated with OS and RFS, underscoring pathological response as a meaningful indicator of true tumor sensitivity to systemic therapy and a potential determinant of long-term outcomes beyond the choice of chemotherapy backbone (21). This interpretation is consistent with the long-term follow-up of DRAGON III, which suggests that the impact of pathological response on survival may outweigh that of regimen selection per se. Therefore, in the era of immunochemotherapy, optimizing perioperative strategies may rely less on switching chemotherapy backbones and more on increasing the likelihood of achieving MPR, for example through more precise patient selection, strengthened perioperative management, and early strategy modification for non-responders. At present, many studies focus on multi-omics data to predict the survival of patients with tumor (22–24), and to accurately manage the treatment strategy of patients, so as to achieve survival benefits. Among them, the prediction model of efficacy response to immunotherapy is the most widely studied. With the progress of research, it can bring more accurate guidance for clinical treatment (25–27).

With respect to safety, the overall incidence of treatment-related adverse events was similar between groups. Although grade ≥3 events were numerically more frequent in the PD-1+FLOT group, the difference was not statistically significant, and no treatment-related deaths occurred. Importantly, operative time and intraoperative blood loss were significantly higher in the PD-1+FLOT group than in the PD-1+SOX group. This may be related to the greater intensity of the triplet regimen, potentially leading to more pronounced myelosuppression and inflammatory responses, increased tissue edema, or fibrosis, thereby complicating surgical exposure and dissection. For frail patients or those with higher perioperative risk, SOX as the chemotherapy backbone in combination with PD-1 blockade may confer an advantage in terms of surgical burden by potentially reducing surgical complexity while maintaining comparable oncological outcomes; however, prospective studies are warranted to confirm causality and elucidate underlying mechanisms.

Several limitations should be acknowledged. First, as a retrospective, single-center study, our analysis is subject to selection bias and residual confounding, and the PD-1 inhibitors used were not fully uniform between groups, which may introduce drug-specific effects. Second, missing data for CPS and MMR limited the robustness of biomarker-based stratification. Third, although no significant differences in OS/RFS were observed, the maturity of follow-up and the number of events may have limited statistical power; larger prospective studies with longer follow-up are needed for confirmation.

In conclusion, in this real-world cohort, neoadjuvant PD-1 inhibitor plus SOX and PD-1 inhibitor plus FLOT demonstrated comparable pathological response, perioperative safety, and OS/RFS, supporting both regimens as reasonable chemotherapy backbones for perioperative immunochemotherapy. PD-1+SOX showed potential advantages in operative time and intraoperative blood loss. More importantly, the independent association of MPR with OS and RFS suggests that pathological response may serve as a key anchor for clinical decision-making and risk stratification. Future prospective studies with standardized biomarker testing are required to define the optimal immunochemotherapy backbone and the patient subgroups most likely to benefit.