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

BACKGROUND AND AIMS: Immune checkpoint inhibitors have revolutionized systemic HCC treatment. Nevertheless, numerous patients are refractory to immune checkpoint inhibitor therapy. It is currently unknown whether diet therapies such as short-term starvation (STS) combined with immune checkpoint inhibitors 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 antitumor immunity of CD8 + T cells as demonstrated in 3 HCC mouse models, NCG mice, and Rag2-KO mice. Furthermore, STS combined with anti-programmed cell death 1/ligand 1 (anti-PD-1/L1) suppressed tumor progression, while the efficacy of 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 2 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.