Huaier Overcomes Tumor-Induced Immunosuppression in Colorectal Cancer by Activating MHC I and CD8+ T Cells

Colorectal cancer (CRC) remains a leading cause of cancer-related mortality, primarily due to its immunosuppressive microenvironment that facilitates immune evasion and resistance to therapy. Although the traditional Chinese medicine Trametes robiniophila Murr (Huaier) has been shown to exert anti-tumor effects, its immunomodulatory potential in CRC and mechanistic interaction with immune checkpoints have not been investigated. Treatment with Huaier significantly improved overall survival in CRC patients (HR=0.682, 95 % CI=0.576-0.809) and reduced tumor burden in both AOM/DSS-induced colitis-associated cancer and subcutaneous models. Notably, Huaier restored intestinal barrier integrity and reprogramed the tumor immune landscape by upregulating the expression of major histocompatibility complex class I (MHC I), which enhanced CD8+ T cell infiltration and cytolytic activity while depleting regulatory T cells. Mechanistically, Huaier activated the STAT1-MHC I pathway, leading to the upregulation of MHC I antigen presentation components, which facilitates the effective recognition of neoantigens by cytotoxic T cells. Crucially, in patient-derived organoids, Huaier synergized with anti-PD-1 therapy, enhancing T cell cytotoxicity. A subcutaneous tumor model was also developed to assess the synergistic effects of Huaier and anti-PD-1, demonstrating that combination therapy exhibited superior efficacy compared to monotherapy. Our findings establish Huaier as a multifaceted immunoadjuvant that bridges innate and adaptive immunity in CRC. This natural agent offers a translatable strategy to enhance the therapeutic efficacy of existing immunotherapies of CRC patients.