Gastric cancer (GC) is a malignancy that accounts for 7.7% of cancer-related fatalities. Globally, it is the fifth most frequently diagnosed cancer and ranks third in cancer-related mortality (1, 2). Although the incidence rate has declined in recent years, there has been an increasing trend in younger populations. GC is characterized by insidious onset, rapid progression, high malignancy, and a poor prognosis (3). Most patients with gastric cancer are already in the advanced stages of the disease at the time of their initial consultation and have lost the opportunity for curative surgery. This implies that more intricate and comprehensive treatment approaches aimed at disease control, symptom alleviation, and improvement in survival quality may need to be developed. Although traditional treatments, such as chemotherapy, can improve overall survival and quality of life, their overall clinical efficacy is limited. The RAINBOW-Asia trial (4) reported a median overall survival of only 7.92 months in patients undergoing chemotherapy alone. Since the latter part of the 20th century, significant progress has been made in leveraging immunotherapy for the management of gastric cancer, particularly through the use of immune checkpoint inhibitors (ICIs). ICIs have become the mainstream treatment for many types of malignant tumors, revolutionizing cancer therapy (5–11). Blocking the PD-1/PD-L1 signaling pathway with immune checkpoint inhibitors plays a crucial role in identifying and preventing the escape of tumor cells. This mechanism improves the tumor microenvironment, stimulates the body’s immune system, enhances immune responses, and effectively eliminates tumor cells. Numerous studies have suggested ICI therapy as a promising therapeutic strategy. Whether used alone or in combination with other treatments such as chemotherapy, ICIs show significant potential in improving the survival of patients with advanced gastric cancer patients (12–15). Tumor mutational burden (TMB) (16), tumor-infiltrating lymphocytes (17), microsatellite instability (MSI) (18), and other tumor biomarkers have been widely studied as predictive biomarkers for PD-1/L1 inhibitor therapy. However, their application in clinical settings is limited because of the relatively complex detection process and the lack of consensus on numerical thresholds. Since Virchow first proposed a potential link between inflammation and tumors, abundant experimental and clinical data have unequivocally established a clear correlation between inflammatory responses and the initiation and progression of tumors (19–21). During chronic inflammation, inflammatory cells release numerous cytokines, chemotactic proteins, and other inflammatory mediators. By activating endogenous or exogenous signals, they alter the cellular microenvironment and promote tumor growth, proliferation, and metastasis. Systemic inflammation is a prominent manifestation of host-tumor interactions in cancer (22, 23) and has been acknowledged as the 7th hallmark of malignant tumors. Building upon this, more scholars have investigated the prognostic value of systemic inflammatory biomarkers, such as the neutrophil-to-lymphocyte ratio (NLR) and monocyte-to-lymphocyte ratio (MLR), in various types of cancer (24–26). The platelet-to-lymphocyte ratio (PLR) is associated with prognosis in many malignant tumors, including non-small cell lung cancer (NSCLC) and breast cancer. The platelet-to-lymphocyte ratio (PLR) has been proven to be associated with prognosis (27, 28). As a straightforward and easily accessible biomarker, PLR can be used to gauge the inflammatory status of the immune system. However, there is currently a lack of meta-analyses on the predictive significance of the PLR and its variations in gastric cancer (GC) patients undergoing immune checkpoint inhibitor (ICI) therapy. Therefore, we included relevant cohort studies to compare the prognosis and treatment response differences in patients with GC with different PLR values after ICI treatment. This study aimed to investigate the prognostic value of the PLR in this patient cohort.

Gastric cancer (GC) is the leading cause of cancer-related fatalities worldwide. Despite notable progress in GC treatment in recent years, persistently high rates of recurrence and mortality prevail (39, 40). The primary challenge stems from the nonspecific nature of early-stage GC detection, with most patients being diagnosed during the advanced stages of cancer. Thus, the identification of biomarkers capable of predicting post-treatment prognosis is of paramount significance for GC treatment. Lymphocytes and platelets play pivotal roles in the systemic inflammatory response, demonstrating crucial functions in tumor development, infiltration, and metastasis (19, 41, 42). Tumor cells employ various mechanisms to activate platelets, leading to the direct release of factors such as IL-1, thrombin, and endothelin, thereby promoting tumor angiogenesis and enhancing tumor migration and dissemination (43). Platelet aggregates encapsulate circulating tumor cells, bolstering their ability to evade host immune attacks (44). Lymphocytes show robust antitumor activity and effectively hinder tumor cell proliferation and metastasis throughout cancer progression (45). A reduced lymphocyte count could result in an inadequate immune response, consequently exerting an adverse impact on the prognosis of patients with solid tumors (46). Platelet-to-lymphocyte ratio (PLR), characterized by its cost-effectiveness and ready accessibility, has garnered widespread attention among scholars. Numerous studies have demonstrated an association between PLR and the prognosis of patients with gastric cancer, including overall survival and progression-free survival (47–50). Tomás and Tiago Cruz (51) affirmed that patients with an elevated PLR have a heightened risk of progression and mortality. Hirahara (52) identified the predictive potential of the combined NLR and platelet-to-lymphocyte ratio (PLR) for treatment outcomes and prognosis in patients with advanced gastric cancer. Tang, Cheng (53) corroborated a substantial association between high PLR and a diminished objective response rate (ORR) in advanced gastric cancer patients following neoadjuvant chemotherapy. Although the Platelet-to-Lymphocyte Ratio has shown prognostic value in diverse cancers, research specifically investigating its prognostic significance in patients undergoing immune checkpoint inhibitor (ICI) therapy is still somewhat limited. A recent retrospective study by Wan M (33), et al. suggested that the PLR and systemic inflammation markers are associated with PFS in patients with gastric cancer receiving immune checkpoint inhibitors (ICIs), while showing no correlation with overall survival (OS). Through univariate and multivariate analyses, Gou (35) concluded that PLR was an independent prognostic factor for both OS and PFS. Additionally, findings from Ziting Qu’s study (37) indicated that PLR acts as an independent prognostic factor for overall survival (OS) in patients with advanced gastric cancer (AGC) undergoing first-line immunotherapy and for PFS in patients undergoing second-line or subsequent immunotherapy. Chen Y (34) suggested a correlation between high PLR, low DCR and ORR. To address this confusion and fill the knowledge gap, we conducted a meticulous meta-analysis of data from nine relevant trials involving 948 patients across two nations. Our study aimed to elucidate whether PLR values could predict the survival outcomes of patients with gastric cancer undergoing immune checkpoint inhibitor (ICI) treatment. In comparison with these studies, our research is the first meta-analysis to incorporate PLR into the analysis of patients with gastric cancer undergoing ICI treatment. Our analysis revealed a discernible trend; elevated PLR values were significantly correlated with reduced survival rates, indicating a significant association between increased PLR and diminished OS and PFS. The combined hazard ratio (HR) for PLR and OS was 1.67, and for PLR and PFS, it stood at 1.51. Furthermore, our subgroup analyses indicated that, irrespective of treatment type (ICIs or ICIs + chemotherapy), sample size (≥100 or <100), cutoff value (>214.08 or ≤214.08), and analysis type (multivariate or univariate), higher PLR values were consistently associated with poorer OS and PFS. The sensitivity analysis and assessment of publication bias also demonstrated the robustness of the results of this meta-analysis. However, there was no statistically significant correlation between PLR and treatment response (ORR/DCR) (ORR: RR = 1.01, p = 0.960; DCR: RR = 0.96, p = 0.319). It is crucial to note that certain limitations should not be overlooked when interpreting our findings. Firstly, the reduction in evidence quality is attributed to the observational and retrospective nature of all included studies, as well as the small sample sizes. Secondly, immune-related adverse events (irAEs) are an inevitable issue that needs to be discussed in the context of immunotherapy. The use of immune checkpoint inhibitors (ICIs) increases the occurrence of irAEs, leading to off-target immune activation and inflammatory reactions. Severe irAEs may necessitate the temporary suspension or dose adjustment of immunotherapy agents, and severe or fatal toxicities pose significant challenges to immunotherapeutic approaches. Due to limitations in the original literature, this study only elucidates the relationship between PLR and overall survival (OS) and progression-free survival (PFS), without revealing the correlation between PLR and irAEs (54, 55). Lastly, since the synthesis of samples is based on studies meeting search criteria, selection bias may be present.

For gastric cancer patients receiving treatment with immune checkpoint inhibitors (ICI), our meta-analysis showed a significant correlation between a higher Platelet-to-Lymphocyte Ratio (PLR) and worse Overall Survival (OS) and Progression-Free Survival (PFS). PLR is a promising prospective biomarker for the prognostication of patients with gastric cancer receiving ICIs. However, considering the limitations of our meta-analysis, larger-scale, multicenter, high-quality prospective trials are needed to validate our results.

The original contributions presented in the study are included in the article/ Supplementary Material . Further inquiries can be directed to the corresponding author/s.

SH: Writing – review & editing, Writing – original draft, Methodology, Formal analysis, Conceptualization. DS: Writing – review & editing, Writing – original draft, Methodology, Conceptualization. YZ: Writing – original draft, Project administration, Data curation. RH: Writing – original draft, Project administration, Data curation. LL: Writing – review & editing, Formal analysis. JZ: Writing – review & editing, Supervision.