DCC-2036 induces repolarization of TAMs to M1 type and enhances CD8(+) T cell immunity in TNBC.

Therapies for triple-negative breast cancer (TNBC) still need innovative approaches, while repolarizing tumor-associated macrophages (TAMs) may offer a breakthrough in the targeted therapy and immunotherapy of TNBC. In this study, our group found that the small-molecule tyrosine kinase inhibitor DCC-2036 could induce repolarization of TAMs from M2 to M1 type and enhance anti-tumor CD8(+) T cell immunity in TNBC. Mechanistically, targeting inhibition of the non-receptor tyrosine kinase hematopoietic cell kinase (HCK) in TAMs regulated the downstream phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT)-mammalian target of rapamycin (mTOR)-glutamine synthetase (GS)-HIF1α signaling pathway, leading to a reprogramming of TAM metabolism from oxidative phosphorylation to glycolysis. This metabolic shift repolarized TAMs to the M1 phenotype, resulting in a decrease in interleukin (IL)-10 secretion, which enhanced the immune response of anti-tumor CD8(+) T cells and increased the sensitivity of TNBC to immune checkpoint blockade therapy. This project uncovers a previously unrecognized anti-tumor mechanism of DCC-2036 and proposes a combination strategy that utilizes DCC-2036 alongside immune checkpoint inhibitors to improve TNBC immunotherapy.