Short-term starvation boosts anti-PD-L1 therapy by reshaping tumor-associated macrophages in hepatocellular carcinoma

Abstract

Background and Aims: Immune checkpoint inhibitors (ICIs) have revolutionized systemic hepatocellular carcinoma (HCC) treatment. Nevertheless, numerous patients are refractory to ICIs therapy. It is currently unknown whether diet therapies such as short-term starvation (STS) combined with ICIs can be used to treat HCC. This study aimed to investigate whether STS could sensitize HCC tumors to immunotherapy. Approach and Results: STS was found to attenuate tumor progression by inducing tumor-associated macrophages (TAMs) to switch to an antitumoral phenotype, enhancing phagocytosis of tumor cells, and stimulating subsequent anti-tumor immunity of CD8+ T cells as demonstrated in three HCC mouse models, NCG mice, and Rag2-KO mice. Furthermore, STS combined with anti-PD1/L1 suppressed tumor progression, while the efficacy of anti-programmed cell death 1 ligand 1 (PD-L1) was improved when combined with STS. Mechanistically, TAM-derived exosomal PD-L1 (exoPD-L1) impairs the efficacy of anti-PD-1/L1. STS attenuates exoPD-L1 secretion from TAM by regulating the fructose diphosphatase 1 (FBP1) /Akt/Rab27a axis. Modulating FBP1/Akt/Rab27a axis potentiates the anti-PD-L1 response using two liposomal delivery systems and macrophage adoptive transfer. Conclusions: This study describes the immunomodulatory effects of STS and provides a rationale for its application as an adjuvant in HCC immunotherapy.