Combretastatin A4-Based Albumin Nanoparticles Remodeling the Tumor Immune Microenvironment to Enhance T Cell Immunotherapy in Colon Cancer.

Abstract

The immunosuppressive tumor microenvironment formed by many solid tumors, particularly colon cancer, suppresses innate immune molecule expression and consequently limits T cell infiltration. Microtubule inhibitors were originally developed to eliminate tumors by inducing mitotic arrest. However, recent studies have shown that these inhibitors can also disrupt the microtubule dynamics and enhance the efficacy of immunotherapies. These findings highlight the target microtubule as a promising strategy for immune modulation. In this study, we investigated the use of Combretastatin A4 (CA4), a hydrophobic microtubule inhibitor that targets tumor vascular endothelial cells. To improve its solubility and delivery efficiency, CA4 was encapsulated in human serum albumin to form CA4@Alb. This formulation effectively inhibited microtubules in tumor endothelial cells, resulting in the promoted infiltration of erythrocytes into the tumor microenvironment. These erythrocytes were subsequently phagocytosed by intratumoral macrophages, leading to their pro-inflammatory activation. Notably, erythrophagocytic macrophages upregulated innate immune molecules, including chemokine CXCL10 and costimulatory molecule CD86, and enhanced T cell infiltration and activation. As a result, CA4@Alb significantly improved the responsiveness to T cell-based immunotherapies. Overall, our findings indicate that CA4@Alb effectively reprograms the immunosuppressive microenvironment of colon cancer and holds promising translational potential for enhancing immunotherapy efficacy.