Abstract
Tumor-associated macrophages (TAM) are a heterogeneous population of myeloid cells that dictate the inflammatory tone of the tumor microenvironment. In this study, we unveiled a mechanism by which scavenger receptor cluster of differentiation 36 (CD36) suppresses TAM inflammatory states. CD36 was upregulated in TAMs and associated with immunosuppressive features, and myeloid-specific deletion of CD36 significantly reduced tumor growth. Moreover, CD36-deficient TAMs acquired inflammatory signatures including elevated type-I IFN (IFNI) production, mirroring the inverse correlation between CD36 and IFNI response observed in patients with cancer. IFNI, especially IFNβ, produced by CD36-deficient TAMs directly induced tumor cell quiescence and delayed tumor growth. Mechanistically, CD36 acted as a natural suppressor of IFNI signaling in macrophages through p38 activation downstream of oxidized lipid signaling. These findings establish CD36 as a critical regulator of TAM function and the tumor inflammatory microenvironment, providing additional rationale for pharmacologic inhibition of CD36 to rejuvenate antitumor immunity. Significance: CD36 in tumor-associated macrophages mediates immunosuppression and can be targeted as a therapeutic avenue for stimulating interferon production and increasing the efficacy of immunotherapy.