Inhibition of the transcription factor PU.1 suppresses tumor growth in mice by promoting the recruitment of cytotoxic lymphocytes through the CXCL9-CXCR3 axis

Tumor-associated macrophages (TAMs) are among the most prevalent immune cells in tumors, often exhibiting immune regulatory phenotypes that promote tumor growth and contribute to resistance against anti-tumor therapies. Consequently, targeting TAMs has emerged as a promising immunotherapeutic strategy aimed at controlling their recruitment or reprogramming, although clinical success remains to be demonstrated. PU.1, a lineage-dependent transcription factor, is consistently expressed throughout the lifespan of macrophages. In our study, we investigated the effects of PU.1 inhibition using the small molecule DB2313 on tumor growth in murine models of melanoma. Our findings indicate that inhibiting PU.1 suppresses the growth of both melanoma. Further analysis in the melanoma model revealed that DB2313 enhances the recruitment of CD4+ T helper cells and cytotoxic T/NK cells into the tumor microenvironment.