Cucurbitacin B induces immunogenic cell death and activates adaptive immunity in cutaneous melanoma via the...

Immunotherapy is the first-line treatment for advanced cases in cutaneous melanoma (CM). However, nearly half of patients develop resistance or recurrence, mainly attributed to an immunosuppressive tumor immune microenvironment (TIME). Cucurbitacin B (CuB), a tetracyclic triterpenoid from Cucurbitaceae plants, has broad-spectrum anticancer activity, yet its role and mechanism in regulating CM-associated immunogenic cell death (ICD) and TIME remain unclear.

To investigate the antitumor effects of CuB on CM, and explore its mechanisms in inducing ICD.

The anti-tumor activity and safety of CuB were evaluated using in vitro and in vivo experiments. Molecular biological assays were performed to detect ICD markers, TIME remodeling, and changes in immune cell subsets. The core mechanism was validated by integrating bioinformatics, molecular techniques, and targeted inhibitors.

1. CuB induces ICD in CM cells with markedly elevated release of damage-associated molecular patterns (DAMPs) both in vitro and in vivo. 2. CuB reprograms the TIME, promotes dendritic cell (DC) maturation, induces macrophage polarization toward the M1 phenotype, enhances effector T cell infiltration, reduces the proportions of myeloid-derived suppressor cells (MDSCs) and regulatory T cells (Tregs), and downregulates PD-L1 expression in tumor tissues and PD-1 expression in splenocytes. 3. Mechanistically, CuB induces ICD via the Reactive oxygen species (ROS)-STAT3-eIF2α/IRE1-mediated endoplasmic reticulum stress (ERS) axis.

CuB is a potential candidate for combination with chemotherapeutics or immune checkpoint inhibitors, offering a novel melanoma treatment strategy.