Immunogenic cuproptosis in cancer immunotherapy via an in situ cuproptosis-inducing system

Cell death-based therapies combined with immunotherapy have great potential in cancer therapy. To further explore and apply the combined therapies, the immunogenicity of different cell death modes in colorectal cancer (CRC) was evaluated by a cause-and-effect framework encompassing 12 cell death modes. Results show robust correlations among cuproptosis, immunogenic cell death (ICD) and immunity in CRC, as observed in our in-house and other independent cohorts, which are substantiated by in vitro and in vivo experiments. Subsequent investigations demonstrate that cuproptosis induces endoplasmic reticulum stress, leading to the release of damage-associated molecular patterns from CRC cells and triggering the maturation of antigen-presenting cells. Moreover, for in vivo therapeutic approaches, an in situ cuproptosis-inducing system was devised, which can further strengthen the effects of immune cells. Through the combined analysis including single-cell RNA sequencing, cuproptosis is shown to mobilize cytotoxic T lymphocytes and M1 macrophages within the tumor microenvironment (TME). Additionally, co-treatment with Imiquimod, the TLR7 agonist, augments the anti-tumor immune responses induced by cuproptosis. Overall, we provide compelling evidence that cuproptosis induces ICD thus fostering an inflammatory TME, and the cuproptosis-based delivery system further promotes this inflammatory environment, demonstrating considerable potential for enhancing tumor therapy efficacy.