Vinburnine potentiates anti-PD1 immunotherapy in melanoma through IL-24 secretion via P38/MAPK/ATF3 signaling.

Abstract

Background: Melanoma, a highly aggressive and immunogenic skin cancer, often develops resistance to immunotherapy due to the immunosuppressive tumor microenvironment (TME). Although PD-1/PD-L1 inhibitors have significantly improved treatment outcomes, 30%-40% of patients exhibit no response or develop resistance. Mechanisms such as T-cell exhaustion within the TME limit therapeutic efficacy, necessitating the exploration of novel strategies to enhance immune responses.

Methods: This study evaluated the effects of Vinburnine (Vin) on melanoma cell proliferation, migration, invasion, apoptosis, and DNA damage through in vitro experiments. Transcriptomic analysis, Western blot, RT-PCR, dual-luciferase reporter assays, and ChIP experiments revealed the mechanism by which Vin regulates IL-24 via ATF3. The anti-tumor efficacy of Vin or IL-24 in combination with PD-1 monoclonal antibody, as well as their modulation of the tumor microenvironment, were validated through luciferase-mediated cytotoxicity assays and a murine melanoma model. Additionally, the correlation between IL-24 expression and patient prognosis or immunotherapy response was analyzed using public databases.

Results: This study delineates the phenotypic mechanisms by which vinburnine suppresses melanoma proliferation. Vin induces reactive oxygen species (ROS) generation, leading to DNA damage and the subsequent activation of the apoptotic cascade in melanoma cells. Additionally, vinburnine activates the P38/MAPK/ATF3 signaling axis, which drives the secretion of interleukin-24 (IL-24), enhancing the functionality of CD8⁺ T cells and modulating the tumor immune microenvironment to favor antitumor immunity. Notably, the combination of vinburnine with anti-PD-1 antibody therapy produces synergistic effects, effectively addressing certain limitations of current immunotherapeutic approaches.

Conclusions: These findings underscore the therapeutic potential of vinburnine, particularly when used in combination with immune checkpoint inhibitors, as a promising strategy for melanoma treatment.