Blocking MARCO+ tumor-associated macrophages improves anti-PD-L1 therapy of hepatocellular carcinoma by promoting the activation of STING-IFN type I pathway

Abstract

The PD-L1/PD-1 axis is a classic immunotherapy target. However, anti-PD-L1/PD-1 therapy alone can not achieve satisfactory results in solid tumors, especially liver cancer. Among the several factors involved in tumor anti-PD-L1/PD-1 treatment resistance, tumor-associated macrophages (TAMs) have attracted attention because of their immunosuppressive ability. TAMs with a macrophage receptor with a collagenous structure (MARCO) are a macrophage subset group with strong immunosuppressive abilities. Clinical specimens and animal experiments revealed a negative correlation between MARCO ⁺ TAMs and patient prognosis with liver cancer. Transcriptional data and in vitro and in vivo experiments revealed that MARCO ⁺ TAM immunosuppressive ability was related to secretion. MARCO suppressed IFN-β secretion from TAMs, reducing antigen presentation molecule expression, infiltration, and CD8⁺T cell dysfunction, thus producing an immunosuppressive microenvironment in liver cancer. MARCO can promote dying tumor cell clearance by macrophages, reducing tumor-derived cGAMP and ATP accumulation in the tumor microenvironment and inhibiting sting-IFN-β pathway activation mediated by P2X7R in MARCO⁺TAMs. Animal experiments revealed that the MARCO and PD-L1 monoclonal antibody combination could significantly inhibit liver cancer growth. Conclusively, targeting MARCO⁺TAMs can significantly improve anti-PD-L1 resistance in liver cancer, making it a potential novel immune target for liver cancer therapy.

Keywords: Hepatocellular carcinoma; IFN-β; MARCO; PD-L1; Tumor-associated macrophages.