SPIN1 Modulates PD-1 Resistance in Gastric Cancer by Influencing Macrophage Polarization

Introduction: Resistance to anti-PD-1 therapy remains a major obstacle to improving outcomes in gastric cancer (GC). Although the chromatin reader SPIN1 has been implicated in tumor progression, its contribution to shaping the tumor immune microenvironment (TIME) and driving immunotherapy resistance is not well understood. This study aimed to elucidate how SPIN1 modulates immune components within the TIME to promote resistance to PD-1 blockade. Experimental Procedures: SPIN1 expression and immune infiltration patterns—including CD8+ T cells, CD163+ and CD206+ macrophages, and TIM-3+ exhausted lymphocytes—were assessed by multiplex immunohistochemistry (mIHC) in GC patients treated with anti-PD-1 therapy. Mechanistic studies were performed using GC cell lines with stable SPIN1 knockdown or overexpression in macrophage co-culture assays, metabolic profiling, and flow cytometric characterization of M1/M2 markers. Antitumor efficacy was evaluated in syngeneic mouse models treated with a SPIN1 small-molecule inhibitor, anti-PD-1 antibody, or the combination. Data Summary: Clinically, SPIN1 expression was significantly higher in non-responders than in responders to PD-1 blockade. Elevated SPIN1 levels strongly correlated with increased infiltration of immunosuppressive M2 macrophages (CD163+/CD206+) and reduced CD8+ T-cell presence in tumor tissue. In vitro, SPIN1 silencing diminished, whereas SPIN1 overexpression enhanced, M2-associated gene expression and surface markers. Flow cytometry confirmed that SPIN1 drives macrophage polarization toward an M2 phenotype. SPIN1-conditioned macrophages subsequently suppressed CD8+ T-cell proliferation and cytotoxic function while inducing T-cell exhaustion, evidenced by increased PD-1, TIM-3, and LAG-3 expression. In vivo, pharmacologic inhibition of SPIN1 reshaped the TIME by reducing M2 macrophage accumulation and restoring CD8+ T-cell infiltration and effector activity. Notably, combining a SPIN1 inhibitor with anti-PD-1 therapy produced a synergistic antitumor response and significantly reversed acquired resistance compared with either single agent. Conclusions: This study identifies SPIN1 as a key regulator of immune suppression and therapeutic resistance in GC. By promoting M2 macrophage polarization and driving CD8+ T-cell exhaustion, SPIN1 establishes a TIME that limits the efficacy of PD-1 blockade. These findings highlight SPIN1 as both a predictive biomarker for immunotherapy response and a promising therapeutic target for sensitizing gastric tumors to PD-1-based immunotherapy. Citation Format: Beibei Lyu, Zijun Yidan Xu-Monette, Xiaoyan lin. SPIN1 drives PD-1 immunotherapy resistance in gastric cancer by inducing M2 macrophage polarization and suppressing CD8+ T-cell immunity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 7014.