Expressed on the surface of phagocytic myeloid cells, SIRPα transmits a “don’t eat me” signal to macrophages when it is engaged by its cognate receptor CD47. Many types of cancer cells aberrantly express CD47 at high levels as a mechanism of immune evasion. CD47 blockade, a therapeutic approach pioneered by the laboratory of Ludwig Stanford Director emeritus Irv Weissman, is therefore being evaluated as a monotherapy and in combination with other agents as a cancer immunotherapy. But SIRPα is also aberrantly expressed on melanoma and other types of cancer cells, though what it does for them has so far been unclear. Researchers led by Ludwig Weill Cornell’s Chien-Huan Weng and Co-directors Jedd Wolchok and Taha Merghoub found that when expressed by melanoma cells, SIRPα suppresses anti-tumor immune responses through an entirely different mechanism: by suppressing CD8+ T cell infiltration into tumors. They described in a May issue of Cell Reports how its deletion in melanoma cells results in the upregulation of the chemokine CXCL10, driving immune infiltration and control of tumor growth. In line with that posited mechanism, CXCL10 deletion suppresses infiltration by CD8+ T cells and accelerates tumor growth. The findings indicate that selective targeting of tumor-expressed SIRPα—which is already being targeted as a potential immunotherapy—might also enhance immune infiltration and T cell-mediated tumor control across SIRPα-expressing cancers.
Tumor-intrinsic expression of signal regulatory protein α contributes to the suppression of anti-tumor immune responses
Cell Reports, 2026 May 29