Tracking interactions between TAMs and CAFs mediated by arginase‐induced proline production during immune evasion of HCC

Abstract Synergistic changes between tumor‐associated macrophages (TAMs) and cancer‐associated fibroblasts (CAFs) aggravated immune evasion of hepatocellular carcinoma (HCC), however, the underlying molecular mechanisms remain elusive. Their continuous and dynamic interactions are subject to bioactive molecule changes. A real‐time and in situ monitoring method suitable for in vivo research of these processes would be indispensable but is scarce. In this study, a dual imaging strategy that tracing the TAMs and CAFs simultaneously was developed using a new arginase‐specific probe and established CAFs‐specific probe. The emerging roles of arginase in mediating CAFs activation in mice were explored. Results showed arginase up‐regulation in TAMs, followed by proline increase. Subsequently, proline produced by TAMs initiated the activation of CAFs. Through the JAK‐STAT signaling, CAFs up‐regulated the PD‐L1 and CTLA‐4, ultimately promoting immune evasion of HCC. This study revealed a new mechanism by which TAMs and CAFs collaborate in immune evasion, providing new targets for HCC immunotherapy.