Transforming “cold” tumors into “hot” ones via immunogenic cell death by bufadienolides for reverse immunosuppressive TME in HCC

Abstract

Hepatocellular carcinoma (HCC) is one of the most common causes of cancer-related death worldwide. Unfortunately, the inherently immunosuppressive tumor microenvironment (TME) severely limits the anti-tumor efficacy of conventional therapies. Immunogenic cell death (ICD) is a rare immunostimulatory form of cell death and can activate adaptive immune responses as a way to remodel the immunosuppressive tumor microenvironment. In this study, we found that bufadienolide-based nanocrystalline formulations (HBE NCs) can reshape the tumor microenvironment by inducing an ICD, thereby achieving superior anti-tumor efficacy. HBE NCs could effectively induce Hepa1–6 cells to release damage-associated molecular patterns, such as CRT as an “eat me” signal, HMGB1 as a “danger” signal and ATP as a “find me” signal to an active immune system. HBE NCs improved the maturation of dendritic cells, enhanced the infiltration of CD4⁺T and CD8⁺T cells, depleted the number of immunosuppressive MDSCs and Treg cells, and successfully reconstructed immunosuppressed “cold” tumors into immune-activated “hot” tumors in HCC mice. Notably, dying Hepa1–6 cells treated with HBE NCs can be used as an in vivo “inactivated vaccine” to effectively enhance the ability of mice to resist the challenge of a live tumor. Our study demonstrates a promising strategy for remodeling the immunosuppressive TME of liver cancer.