Absence of BCAP in myeloid cells abrogates M2 macrophage differentiation and promotes anti-tumor immunity.

B-cell adaptor for PI3K (BCAP) is a critical signaling adapter that links Toll-like receptors (TLRs) to the phosphatidylinositol 3-kinase (PI3K)-Akt pathway and negatively regulates TLR-induced inflammation. BCAP also facilitates transition of macrophages from an inflammatory (M1) to a reparatory (M2) state; however, whether BCAP functions downstream of receptors that directly drive M2 macrophage differentiation is not known. Here, we find that BCAP is essential for M2 differentiation in response to interleukin (IL)-4 and IL-33. BCAP-deficient macrophages displayed an impaired M2 gene program, marked by reduced expression of Arg1, Retnla, and Mgl2. Mechanistically, BCAP enables IL-4-driven PI3K-Akt activation by mediating interactions between p85 and Grb2 without impacting STAT6 function. Strikingly, loss of BCAP, either globally or in myeloid cells, leads to suppressed tumor growth and a shift in tumor-associated macrophages toward a pro-inflammatory state and less exhausted tumor-infiltrating CD8 T cells. These findings present BCAP as a promising therapeutic target for enhancing anti-tumor immunity.