TRIM32 promotes tumor immune evasion and impedes Anti-PD-1 treatment by inducing immunosuppressive macrophages in gastric cancer.

BACKGROUND: The tumor microenvironment (TME) in gastric cancer (GC) exhibits immunosuppressive features that facilitate tumor advancement and obstruct the effectiveness of immunotherapy. The role of tripartite motif 32 (TRIM32) in the TME has not been extensively studied. METHODS: GC mouse model was utilized along with flow cytometry analysis, transwell assays, and immunohistochemistry to investigate the impact of TRIM32 on tumor progression and macrophage. To uncover the mechanisms by which TRIM32 operates within the GC microenvironment, various molecular and biochemical methods were utilized, including RNA-sequencing, western blotting, quantitative reverse transcription-polymerase chain reaction, coimmunoprecipitation, and immunofluorescence. RESULTS: TRIM32 originating from tumors was found to be linked to poor prognosis and notably associated with tumor-associated macrophages (TAMs) in. In vitro experiments revealed that TRIM32 induced TAMs recruitment and M2-like polarization. Mechanismly, TRIM32 interacted with Phosphodiesterase 9 A (PDE9A) and activated the downstream phosphatidylinositol-3-kinase/protein kinase B (PI3K/Akt) signaling pathway. Additionally, the reprogramming of TAMs by TRIM32 diminished the resistance to anti-PD-1 treatment in GC models. CONCLUSION: TRIM32/PDE9A axis promotes immune evasion in tumors and hinders the effectiveness of anti-PD-1 treatment by inducing TAMs recruitment and M2-like polarization in GC. This research provides insight into the role of TRIM32 in modulating tumor immunity and suggests that TRIM32 could be a promising target to overcoming resistance to anti-PD-1 therapy in GC.