Activation of thermogenic adipose tissue reverses antitumor resistance of immunotherapy by recruiting intratumoral cytotoxic T cells

Anticancer immunotherapy has emerged as an effective therapeutic modality and is widely used in the clinic for treatment of various human cancers. However, clinical benefits of immune checkpoint inhibitor (ICIs)-based immunotherapy are generally limited. Here, we show that in various mouse tumor models thermogenic adipose tissue activation (TATA) by cold exposure or 3-adrenoceptor agonists markedly improved tumor recruitment of cytolytic T cells. TATA effectively converted immune-desert tumors into immune-infiltrated tumors and reverted ICI-resistant tumors to become sensitive tumors. Mechanistically, a combination of unbiased and integrated proteomic and Single-cell RNA sequencing approaches discovered the TAT-decorin-TAM-CXCL9 signaling axis in recruitment of T cells in tumors. Pharmacological inhibition of CXCL9, genetic deletion of macrophages, and macrophage specific deletion of the Cxcl9 gene, and decorin knockdown in mice completely neutralized the TATA-enhanced immunotherapy. Recruitment of tumor CXCL9+ TAMs was dependent on TATA and debilitation of TAT by surgical removal or genetic deletion of UCP1 abolished this effect. In several ICI-resistant tumors, including colorectal cancer and triple negative breast cancer models, a combination of TATA and ICIs produced synergistic antitumor effects. Together, our findings provide a new concept and paradigm for effective treatment of cancer by combination of TATA and anticancer immunotherapy.