Over recent years, immune checkpoint inhibitors (ICIs) have become the backbone of therapy across multiple malignancies, elevating 5-year overall survival (OS) to 31.9% in advanced non-small-cell lung cancer (NSCLC) and yielding 48.3% 5-year relapse-free survival when combined with targeted therapy in BRAF-mutant melanoma (1, 2). Nevertheless, clinical practice still faces formidable challenges: the non-response rate to immunotherapy varies markedly across cancer types, reaching 30% in first-line immune-chemotherapy for advanced esophageal carcinoma, while recurrent or metastatic head and neck squamous cell carcinoma (HNSCC) achieves a median progression-free survival (PFS) of only 3.4 months with single-agent ICI; moreover, approximately 10–15% of patients develop grade ≥3 immune-related adverse events such as pneumonitis or myocarditis (3–5). Evidence indicates that inter-individual heterogeneity in inflammatory-immune homeostasis within the tumor microenvironment (TME) constitutes a central driver of therapeutic variability.

Tumor-associated inflammation, a hallmark of malignancy, is intimately linked to tumor progression and therapeutic response. Neoplastic cells, together with stromal components such as tumor-associated macrophages and cancer-associated fibroblasts, continuously release IL-6, TNF-α, GM-CSF, thereby establishing a chronic inflammatory milieu (6). Among these, IL-6 markedly impairs CD8⁺ T-cell function via JAK/STAT3 pathway activation; studies show that JAK/STAT3 signaling reduces T-cell proliferative capacity by 40–60% (7). Meanwhile, IL-6 also facilitates regulatory T-cell (Treg) differentiation; in vitro, Treg proportions increase approximately 2.3-fold when IL-6 exceeds 10 pg/mL, thereby intensifying immunosuppression (8). Under tumor-associated inflammation, the infiltrating fraction of M2-polarized tumor-associated macrophages can reach 60% of total TAMs, a proportion more than ten-fold higher than that in adjacent non-malignant tissues (9). These cells directly suppress effector T-cell function via TGF-β secretion, and their density correlates inversely with ICI response (10). Upregulation of vascular endothelial growth factor (VEGF) driven by inflammatory cytokines represents a hallmark of tumor-associated inflammation. Serum VEGF levels in patients with advanced malignancies are elevated, with mean concentrations approximately 5.8-fold higher than those in healthy individuals (11). VEGF not only promotes tumor angiogenesis but also impedes lymphocyte infiltration into the tumor core by forming a vascular barrier, thereby compromising the potential efficacy of immunotherapy (12).

The platelet-to-lymphocyte ratio (PLR) is a composite index that has received considerable attention in recent years. It is calculated as the platelet count divided by the absolute lymphocyte count, and can reflect information on both inflammation and tumor immunity. On one hand, GM-CSF in the tumor microenvironment can activate the aryl hydrocarbon receptor (AHR) pathway in macrophages, upregulate thrombopoietin (TPO) expression, and increase the peripheral blood platelet count (13). Activated platelets not only exacerbate immunosuppression by releasing IL-6 and TGF-β but also bind to CD44 on tumor cell surfaces, thereby promoting tumor metastasis (14). On the other hand, the persistent inflammatory state induces lymphocyte apoptosis and increases the proportion of exhausted CD8⁺ T-cell subsets, thereby weakening the anti-tumor immune response (15).

However, the clinical predictive value of PLR remains controversial. In lung cancer, a 2019 retrospective study demonstrated that patients with PLR ≥180 had a median progression-free survival (mPFS) that was 4.4 months shorter than those with PLR <180, with an overall survival (OS) hazard ratio (HR) of 2.239 (95% CI: 1.478-3.392). In contrast, a single-center retrospective study focusing on BRAF wild-type metastatic melanoma found no such association; in that study, PLR showed no statistical correlation with patient OS (HR = 1.00, 95% CI: 0.99-1.01, P = 0.87) and demonstrated no prognostic value in either univariate or multivariate analysis (16, 17). The core of this discrepancy lies in the fact that PLR’s predictive efficacy is influenced by multiple factors. First, differences in cancer types and tumor microenvironment (TME) contribute to varied immunologic contexts across malignancies, leading to inconsistent associations with PLR. Second, therapeutic regimens and types of immune checkpoint inhibitors (ICIs) play a role: treatments such as ICI monotherapy versus combinations with chemotherapy or anti-angiogenic agents may alter PLR baseline levels, while distinct mechanisms of anti-PD-1/PD-L1 versus anti-CTLA-4 agents may lead to differential interactions with PLR. Third, variations in demographic and geographic factors—including genetic background, baseline immune status, and treatment strategies between Eastern and Western populations-may result in divergent PLR cutoff selections and predictive performance. Therefore, this study aims to systematically evaluate and perform a meta-analysis to clarify the overall impact of PLR on survival outcomes in cancer patients receiving immunotherapy, while using subgroup analyses to examine whether cancer type, treatment strategy, ICI class, and geographic region represent sources of heterogeneity, ultimately providing comprehensive evidence to support the clinical application of PLR.

The advent of cancer immunotherapy has brought revolutionary breakthroughs in the treatment of solid tumors. Immune checkpoint inhibitors, particularly PD-1/PD-L1 inhibitors, have demonstrated survival benefits across multiple malignancies including NSCLC, renal cell carcinoma, and melanoma. For instance, the 5-year survival rate for advanced NSCLC patients receiving ICIs has increased to 15%-20%, far surpassing the <5% rate observed in the chemotherapy era (116). However, clinical practice continues to face two major challenges. First, the efficacy of ICIs demonstrates significant heterogeneity, with only 20%-40% of patients achieving sustained responses. The remaining patients may experience treatment discontinuation due to primary resistance, an immunosuppressive tumor microenvironment, or immune-related adverse events (irAEs) (117). Second, PD-L1 expression testing is hampered by issues such as differences in antibody clones and false negatives caused by tumor heterogeneity. Tumor mutational burden (TMB) testing is characterized by high costs and long turnaround times, limiting its widespread adoption in primary care settings. Meanwhile, microsatellite instability-high (MSI-H) or mismatch repair deficiency (dMMR) is predominantly observed in only a few cancer types, such as colorectal and endometrial cancers, and cannot fulfill the need for pan-cancer prognostic assessment (118–120). Consequently, there is an urgent need to identify novel biomarkers. The PLR, as a peripheral blood marker reflecting systemic inflammatory and immune balance, represents a promising direction for further investigation.

The prognostic value of PLR is hypothesized to reflect the complex interplay between systemic inflammation and tumor immunity. Although direct mechanistic links were not evaluated in the included clinical studies, we speculate that activated platelets might release cytokines such as platelet-derived growth factor (PDGF) and transforming growth factor-β (TGF-β). These factors could theoretically facilitate tumor angiogenesis and potentially foster an immunosuppressive microenvironment by recruiting myeloid-derived suppressor cells (MDSCs) and regulatory T cells (Tregs), which might inhibit the function of CD8⁺ cytotoxic T cells (121, 122). Concurrently, an elevated PLR is often accompanied by reduced lymphocyte counts, which can directly determine the intensity of the immune response (123). Previous single-center studies have preliminarily confirmed the association between high PLR and poor outcomes following ICI therapy. For instance, a study by Xu et al. showed that patients with PLR ≥170 had a 102% increased risk of shorter median OS compared to those with PLR <170 (HR = 2.02, 95% CI: 1.46 to 2.80), and a 74% increased risk of shorter PFS (HR = 1.74, 95% CI: 1.27-2.38) (124). However, these studies were mostly limited to single cancer types or single ICI classes, and the lack of a unified PLR cutoff value hindered cross-study comparisons and the ability to define its prognostic value across different treatment lines and tumor stages (125, 126). Furthermore, systematic evidence is still lacking regarding the differential prognostic role of PLR for specific ICIs (e.g., nivolumab) across various cancer types, as well as its synergistic predictive power combined with other inflammatory markers, which significantly limits the clinical translation of PLR.

This systematic review and meta-analysis, encompassing 98 studies and patient data across 10 cancer types, aimed to address these research gaps. The results demonstrated that elevated PLR consistently served as a risk factor for OS in various malignancies, including NSCLC, gastrointestinal cancers, urological cancers, and renal cell carcinoma, significantly shortening OS. The association was most pronounced in esophageal carcinoma (HR = 2.08, 95% CI: 1.13-3.83) and hepatocellular carcinoma (HR = 2.10, 95% CI: 1.43-3.08), a finding consistent with the chronic inflammatory microenvironment characteristic of these cancers (127). Esophageal carcinoma patients often present with long-standing esophageal mucosal inflammation, while hepatocellular carcinoma patients frequently have underlying viral hepatitis or cirrhosis, resulting in a high baseline inflammatory burden. Elevated PLR, as a manifestation of systemic inflammation, may reflect an immunosuppressive microenvironment that undermines ICI efficacy (128–130). Notably, no statistically significant difference was reached in the OS subgroup for triple-negative breast cancer, potentially related to the immunogenic heterogeneity of TNBC. Some TNBC patients harbor BRCA mutations or high TMB, whose robust immune responses might counteract the negative impact of high PLR (131–133).

Regarding progression-free survival, the prognostic value of elevated PLR demonstrated significant cancer-type specificity: high PLR was significantly associated with shortened PFS in NSCLC (HR = 1.59, 95% CI: 1.27-1.99), hepatocellular carcinoma (HR = 1.78, 95% CI: 1.36-2.34), and esophageal carcinoma (HR = 1.67, 95% CI: 1.08-2.59). However, this association did not reach statistical significance in renal cell carcinoma (HR = 1.60, 95% CI: 0.97-2.62). This discrepancy may be attributed to differences in cancer biology. RCC patients receiving ICI therapy are prone to pseudoprogression, potentially introducing assessment bias in radiological PFS evaluation (134, 135). Furthermore, the non-significant PFS result in the main RCC analysis contrasted with the robust correlation observed in the nivolumab-treated RCC subgroup. This divergence likely stems from the masking effect of pharmacological heterogeneity; the inclusion of various ICIs in the main analysis may have diluted the specific prognostic signal. In contrast, the more homogenous nivolumab-RCC subgroup unmasked the potent prognostic utility of PLR for this specific agent. In TNBC patients, fluctuations in lymphocyte counts due to chemotherapy-induced myelosuppression may obscure the relationship between PLR and PFS, necessitating further investigation (136, 137).

Subgroup analysis by ICI type further revealed potential mechanistic interactions between PLR and different inhibitors. Among patients receiving camrelizumab, high PLR demonstrated the most pronounced effect on OS reduction (HR = 4.68, 95% CI: 2.95-7.45), whereas the associations were more moderate in nivolumab and pembrolizumab subgroups (HR = 1.77 and 1.66, respectively). We speculate that this discrepancy might be partially related to camrelizumab’s structural features, such as its Fc segment properties. It is hypothesized that in patients with high PLR, the elevated systemic inflammatory burden might interfere with the immune-modulatory effects of specific antibodies, although this requires further biological validation (138, 139). In contrast, nivolumab and pembrolizumab primarily modulate the immune microenvironment through direct CD8⁺ T-cell activation, and high PLR might exert a general inhibitory effect on this process, resulting in more consistent PFS outcomes across ICI subgroups (140). Notably, nivolumab demonstrated unique prognostic value for PLR in the RCC subgroup (OS: HR = 2.31, 95% CI: 1.86-2.86; PFS: HR = 1.63, 95% CI: 1.33-2.01), but not in NSCLC or esophageal carcinoma subgroups. This may be hypothetically linked to RCC’s characteristic VEGF overexpression (141). It is suggested that platelet-derived factors might contribute to angiogenesis, potentially creating barriers to immune cell infiltration. Phase III clinical trials have confirmed that nivolumab combined with anti-VEGF agents can disrupt this cycle and improve RCC outcomes, suggesting that RCC patients with high PLR may be more suitable for ICI plus anti-VEGF combination therapy (142, 143). Beyond single inflammatory indices, composite markers like the C-PLAN index (comprising CRP, PLR, Albumin, and NLR) have recently demonstrated superior prognostic accuracy in nivolumab-treated RCC by integrating multiple systemic pathways. While PLR specifically reflects the balance between thrombocytosis-driven tumor promotion and lymphocytic immune surveillance, composite scores like C-PLAN may offer incremental value by incorporating nutritional status and acute-phase reactants, providing a more comprehensive reflection of the tumor-host interface in RCC (144).

Subgroup analyses by treatment line and tumor stage further expand the clinical applicability of PLR. Elevated PLR was consistently associated with reduced OS/PFS regardless of whether patients received first-line or second-line (and beyond) ICI therapy, though some outcomes in the second-line subgroup (e.g., OS in urological cancers) did not reach statistical significance. This may be attributed to poorer baseline performance status and confounding effects from prior radiotherapy or chemotherapy in later-line patients. These findings suggest that patients with high pre-treatment PLR in the first-line setting may harbor primary immune resistance risks, warranting consideration for initial ICI-chemotherapy combinations to enhance efficacy. For second-line therapy, elevated PLR reflects inflammation-immune imbalance exacerbated by previous treatments, necessitating shorter radiological assessment intervals for early progression detection. In tumor stage subgroup analysis, the prognostic impact of high PLR was more pronounced in stage IV patients, while earlier-stage subgroups (e.g., II-IV) showed relatively modest effects. This discrepancy may stem from advanced cancer patients frequently exhibiting more severe systemic inflammatory responses and pre-cachectic states, where PLR as an integrative inflammatory marker better reflects overall immune suppression. Conversely, early-stage patients with lower tumor burden experience less tumor-driven inflammation, diminishing PLR’s predictive weight. This underscores the need for dynamic interpretation of PLR values in context with tumor staging. Furthermore, our analysis revealed similar hazard ratios for the subgroups defined by different PLR cutoffs (e.g., <180 vs. ≥180). This similarity suggests that PLR likely functions as a continuous prognostic risk factor rather than exhibiting a distinct “cliff effect” at a specific numerical threshold. Consequently, the clinical implication is that a progressive elevation in PLR signals a generally worsening prognosis; therefore, clinical decision-making should consider the overall trend of inflammatory burden rather than relying solely on a single rigid cutoff point.

This study has several limitations: (1) The included studies were predominantly retrospective in design, introducing potential selection bias; variations in the completeness of records regarding patient comorbidities and prior treatment history may affect the stability of the results. (2) The lack of a standardized cutoff value for PLR, with differing risk stratification thresholds across studies, may lead to bias in effect size calculations and weaken cross-study comparability. (3) Therapeutic coverage for certain malignancies is constrained by data availability; for instance, while RCC has numerous frontline options, eligible studies reporting PLR-stratified HRs were largely restricted to nivolumab-based regimens. This scarcity of data on newer ICI-TKI combinations may limit the generalizability of PLR’s prognostic utility across the entire current RCC treatment landscape. (4) A critical limitation is that, as the included primary studies predominantly reported results in the form of categorical variables (high vs. low), we were unable to access raw data to conduct analyses treating PLR as a continuous variable. This constraint inevitably leads to a loss of information regarding the linear dose-response relationship and prevents the establishment of a precise prognostic nomogram. (5) Due to the lack of direct biological measurements in the included studies, the mechanistic explanations discussed herein (e.g., regarding specific cytokines or cellular interactions) remain speculative and hypothesis-generating. Future translational research is needed to causally validate these pathways. (6) Only the prognostic role of baseline PLR was explored, without incorporating dynamic changes in PLR during treatment. Based on these limitations, future research should focus on three key directions: (1) Conducting multicenter prospective cohort studies with standardized PLR measurement timing and cutoff values. (2) Designing longitudinal study protocols to analyze the association between the magnitude of PLR reduction after 2–4 treatment cycles and ICI efficacy. (3) Integrating basic science experiments with clinical samples to investigate the molecular mechanisms through which PLR modulates the tumor microenvironment.

This study demonstrates that elevated baseline platelet-to-lymphocyte ratio is associated with poor prognosis in cancer patients receiving immune checkpoint inhibitors, manifested as significantly shortened overall survival across most cancer types and reduced progression-free survival in specific malignancies including non-small cell lung cancer, hepatocellular carcinoma, and esophageal carcinoma. This prognostic value is particularly prominent in renal cell carcinoma patients treated with nivolumab, advanced gastrointestinal cancer patients, and those receiving first-line ICI therapy. As an inexpensive and readily accessible peripheral blood marker, PLR holds clinical significance for initial prognostic stratification in ICI-treated patients. However, multicenter randomized controlled trials are warranted to establish optimal PLR cutoff values for different cancer types, validate the prognostic significance of dynamic PLR changes, and further explore its prognostic implications across various malignancies.