Tumor-intrinsic expression of signal regulatory protein α contributes to the suppression of anti-tumor immune responses

<h2>Summary</h2> SIRPα is a well-characterized inhibitory receptor on myeloid immune cells. However, human and mouse melanoma cells can also express high levels of SIRPα. Whether and how melanoma cell-intrinsic SIRPα contributes to tumor progression and anti-tumor immunity remains underexplored. Here, we identify a role of tumor cell-intrinsic SIRPα in suppressing immune recruitment and activation. SIRPα deletion in melanoma cells enhances tumor control and increases immune infiltration. Transcriptomic analyses reveal that loss of tumor cell-intrinsic SIRPα upregulates the chemokine CXCL10 in both human and mouse melanoma cells. Notably, <i>Cxcl10</i> knockdown in SIRPα-deficient melanoma partially rescues tumor growth and reduces CD8⁺ T cell infiltration, mirroring the phenotype of SIRPα-expressing tumors and indicating that tumor cell-intrinsic SIRPα promotes immune evasion by suppressing <i>Cxcl10</i>-mediated T cell recruitment. Our study uncovers an unrecognized mechanism of SIRPα-mediated immune suppression and highlights SIRPα silencing as a potential therapeutic strategy to enhance immune infiltration and T cell-mediated tumor control across SIRPα-expressing cancers.