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

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. 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. This study describes the immunomodulatory effects of STS and provides a rationale for its application as an adjuvant in HCC immunotherapy.