β-glucan elicits APOE-dependent peripheral trained immunity to suppress hepatocellular carcinoma

Although immunotherapy has revolutionized cancer treatment, hepatocellular carcinoma (HCC) continues to demonstrate limited clinical responses, highlighting the urgent need for novel immunomodulatory strategies. Trained immunity, an emerging paradigm wherein innate immune cells develop a memory-like phenotype through epigenetic and metabolic reprogramming, offers a promising avenue to remodel the immunosuppressive tumor microenvironment. This study investigated whether β-glucan-induced trained immunity could potentiate antitumor immunity against HCC.

We established orthotopic HCC mouse models to investigate the role of trained immunity induced by whole β-glucan particle (WGP) in the HCC microenvironment, particularly in modulating hepatic apolipoprotein E (APOE)-positive monocytes/macrophages. Transcriptional changes in trained monocytes/macrophages were identified by analyzing single-cell RNA sequencing and bulk RNA-sequencing data from the livers of WGP-treated and control mice. Mechanistic studies were performed using Apoe ^-/- mice and in situ monocyte/macrophage engineering. Flow cytometry was performed to assess immune cell phenotypes and phagocytosis, while luminescence-based assays were used to evaluate cytotoxic activity. The translational potential was assessed using human monocyte training assays.

This study demonstrated that preconditioning with WGP, a trained immunity inducer, increased the accumulation of trained monocytes/macrophages in the liver and suppressed tumor progression in HCC mouse models. Mechanistically, WGP-trained APOE⁺ monocytes/macrophages exhibited a decrease in lipid accumulation and endoplasmic reticulum stress, thereby enhancing their antitumor function. Genetic deletion of Apoe in monocytes/macrophages abrogated the antitumor effects of WGP, demonstrating that APOE⁺ monocytes/macrophages are essential mediators of WGP-induced trained immunity. Adoptive transfer of WGP-trained bone marrow-derived macrophages suppressed the growth of HCC in recipient mice. Furthermore, WGP induced trained immunity in human monocytes, leading to enhanced killing of HCC cells. Notably, combination therapy with WGP and anti-programmed death-ligand 1 antibody achieved superior tumor control compared with either monotherapy.

These findings identify a critical role for trained APOE⁺ monocytes/macrophages in WGP-mediated antitumor immunity in the liver. Harnessing WGP-induced peripheral trained immunity represents a novel therapeutic strategy for HCC.