Cisplatin priming enhances anti-PD-L1 therapy in oral squamous cell carcinoma via sequence-associated remodeling of the tumor immune microenvironment

Introduction Neoadjuvant chemoimmunotherapy has emerged as a promising strategy for locally advanced oral squamous cell carcinoma (OSCC), yet the optimal platinum agent and administration sequence with immune checkpoint blockade remain unclear. This study investigated whether different platinum agents exert distinct immunomodulatory effects and whether treatment sequencing determines the efficacy of cisplatin combined with anti-PD-L1 therapy. Methods The cytotoxic and immunomodulatory effects of cisplatin (CDDP), carboplatin (CBP), and oxaliplatin (OXP) were compared in MOC1, MOC2, and CAL27 OSCC cells. Cell viability, immunogenic cell death (ICD)-related molecules, and PD-1/PD-L1-related expression were assessed using CCK-8 assays, western blotting, and immunofluorescence. An immunocompetent MOC1 subcutaneous tumor model was then used to compare CDDP monotherapy, anti-PD-L1 monotherapy, CDDP followed by anti-PD-L1, anti-PD-L1 followed by CDDP, and concurrent combination therapy. Tumor growth, systemic toxicity, ICD-related protein expression, immune checkpoint exposure, immune-cell infiltration, T-cell function, and macrophage polarization were analyzed. Patient-derived OSCC organoids from three patients were used for exploratory assessment of sequence-dependent treatment responses. Results CDDP showed the greatest reduction in cell viability among the three platinum agents and induced the most prominent upregulation of CRT, HMGB1, and PD-1/PD-L1-related molecules, suggesting CDDP may be accompanied by enhanced ICD-related immunogenic stress and checkpoint target exposure. In vivo , CDDP followed by anti-PD-L1 showed the greatest numerical tumor inhibition, reducing terminal tumor volume by 56.1% versus PBS, 45.4% versus CDDP alone, and 33.8% versus anti-PD-L1 alone; terminal tumor weight was reduced by 39.7% versus PBS. This sequence showed favorable tolerability. Immune profiling showed that CDDP followed by anti-PD-L1 was associated with remodeling of the tumor immune microenvironment, characterized by reduced Tregs and CD206 + M2-like macrophages, restoration of CD86 + M1-like macrophages and increased IFN-γ + CD8 + T-cell activity. In two of the three patient-derived organoid models, chemotherapy followed by ICI produced the greatest reduction in organoid viability. Conclusion CDDP may serve as an immune-priming platinum agent in OSCC. Sequential CDDP followed by anti-PD-L1 therapy showed a favorable tumor growth inhibition trend among the tested schedules, accompanied by sequence-dependent changes in the tumor immune microenvironment, suggesting that treatment timing may influence response patterns during neoadjuvant chemoimmunotherapy in OSCC.