Tumor-intrinsic expression of signal regulatory protein α (SIRPα) contributes to the suppression of anti-tumor immune responses [RNA_CD172KO]

Signal regulatory protein α (SIRPα) is a well-characterized inhibitory receptor expressed on myeloid immune cells. We and others have recently discovered that human and mouse melanoma cells express high levels of SIRPα. However, whether and how melanoma-intrinsic SIRPα contributes to tumor progression and anti-tumor immunity remains underexplored. Here, we identify a novel role of tumor-intrinsic SIRPα in suppressing anti-tumor immune recruitment and activation. Genetic deletion of SIRPα in melanoma cells enhanced tumor control and increased infiltration of immune cells into the tumor. Transcriptomic analysis revealed that loss of melanoma cell-intrinsic SIRPα leads to upregulation of C-X-C motif chemokine 10 (CXCL10) expression in both human and mouse melanoma cells. Notably, knockdown of Cxcl10 in SIRPα-deficient melanoma cells partially rescued tumor growth and reduced CD8+ T cell infiltration, recapitulating the phenotype observed in SIRPα-expressing tumors. These findings indicate that tumor cell-intrinsic SIRPα suppresses anti-tumor immunity by inhibiting Cxcl10 expression, thereby compromising T cell recruitment to the tumor sites. Thus, our work uncovers a previously unrecognized mechanism by which melanoma cell-intrinsic SIRPα suppresses anti-tumor immunity and highlights the therapeutic potential of silencing SIRPα to enhance anti-tumor immune cell infiltration and promote T cell-mediated tumor control. We envision that SIRPα silencing as a therapeutic strategy that could be applied to other cancer types that express SIRPα.