Concurrent induction of pyroptosis and immunogenic cell death by capsaicin/graphene nanocomplex for enhanced breast cancer immunotherapy

Inducing immunogenic cell death (ICD) has emerged as a promising strategy for targeting immunologically "cold" tumors. However, most current therapies focus on a single mechanism, limiting their efficacy. In this study, we propose a nano-enabled approach that synergistically activates two complementary immunogenic killing mechanisms: pyroptosis, which elicits a potent inflammatory response, and ICD, characterized by the presentation of 'eat-me' signals and tumor antigens to the immune system. Capsaicin, a naturally occurring compound, was employed to induce pyroptosis via ROS-mediated gasdermin E (GSDME) cleavage, resulting in cell membrane blebbing and subsequent cell death. To simultaneously trigger ICD, we incorporated 2D graphene oxide (GO) engineered with optimized physicochemical properties to induce robust ICD under near-infrared irradiation. Our in vitro and in vivo experiments demonstrated that the combined treatment of capsaicin and GO not only enhanced cancer cell killing but also promoted immune cell infiltration and potentiated anti-tumor immunity, leading to significant tumor suppression. Moreover, the dual-trigger mechanism of pyroptosis and ICD yielded superior anti-tumor efficacy compared to single-modality treatments while maintaining a favorable biosafety profile. These findings highlight the potential of a synergistic nano-enabled strategy for improving cancer immunotherapy.Graphical AbstractConcurrent Pyroptosis and ICD Induction via Cap/GO Synergy Enhances Anti-Tumor Immunity. The Cap/GO complex combines ROS-mediated pyroptosis (via Cap) with ICD activation (via GO under NIR irradiation), fostering an immunological tumor microenvironment. Pyroptosis triggers IL-6 and IL-1 beta, while ICD exposes CRT and HMGB1. This synergy drives T-cell infiltration, amplifying anti-tumor immunity and achieving robust tumor suppression.