Cold-inducible brown fat thermogenesis enhances MHC class I expression and antitumor immunity in ovarian cancer.

Brown adipose tissue (BAT) thermogenesis, induced by cold exposure or ß3-adrenergic receptors (ß3AR) agonist, decreases tumor glucose availability and arrests tumor progression. However, the effect of BAT activation on tumor metabolic reprogramming, the tumor microenvironment (TME), and the possibility of in combination with immunotherapy has not been defined. Here, we found that cold-inducible BAT thermogenesis promoted an anti-Warburg metabolic shift that reshaped TME characterized by accumulation of tumor-infiltrating CD8+ T cells (CD8+ TILs) with effector-like and memory phenotype and proinflammatory macrophages. Consistently, combination treatment with anti-PD-1 and cold exposure or ß3AR agonist, strongly inhibited tumor growth or complete regressions across multiple preclinical mouse models. Therefore, BAT thermogenesis by cold exposure or ß3aR agonist, highlighting a promising therapeutic approach to increase tumor immunogenicity and improve immunotherapy efficacy. Overall design: Comparative gene expression profiling analysis of RNA-seq data for tumor tissues, sorted tumor cells, and sorted CD8+T cells from HM1 tumors under 30 °C and 4 °C.