TRIM2 facilitates macrophage mediated anti-tumor immunity in renal cell carcinoma through enhancing SIRPA ubiquitination and degradation

Abstract SIRPA delivers an anti-phagocytic “don’t-eat-me” signal through its expression on macrophage membrane surface and promotes tumor progression via membrane-independent mechanism. However, current CD47- and SIRPA-targeting agents only disrupt cell-surface inhibitory signaling, highlighting the therapeutic potential of degrading SIRPA. Here, we identified that E3 ubiquitin ligase TRIM2 interacted with SIRPA in vitro. Clinically, elevated TRIM2 expression is associated with prolonged overall and progression-free survival in renal-cell carcinoma (RCC) patients. Mechanistically, TRIM2 catalyzes K48-linked poly-ubiquitination of SIRPA, promoting its proteasomal degradation and reducing SIRPA protein levels. CRISPR/Cas9-mediated deletion of TRIM2 in macrophages upregulated SIRPA, significantly impairing phagocytosis of tumor cells. TRIM2 deficiency also promoted tumor growth by increasing intratumoral infiltration of M2-type macrophage, reducing accumulation of anti-tumor M1-like and antigen-presenting macrophages, and impairing effector CD8 + T-cell recruitment. Importantly, combined TRIM2 overexpression and PD-L1 blockade synergistically enhance anti-tumor immunity. Together, these results suggest that targeting TRIM2 may represent a novel therapeutic strategy against RCC by degrading SIRPA in macrophage and provide a roadmap for clinical application.