TMTP1-modified nanocarrier boosts cervical cancer immunotherapy by eliciting pyroptosis

<b>Rationale:</b> Pyroptosis, an emerging form of programmed cell death, facilitates the release of tumor antigens and inflammatory factors, which can be leveraged to enhance the efficacy of immune checkpoint blockade (ICB) therapy. However, achieving high-efficiency induction of pyroptosis in cancer cells while minimizing toxicity remains a significant challenge. <b>Methods:</b> In this study, we designed a tumor-targeting peptide TMTP1-modified nanostructured lipid carrier (referred to as TP-NLC) with high loading capacities for gambogic acid (GA) and indocyanine green (ICG). The TMTP1, identified by our research team for its tumor-targeting capabilities, was conjugated to the nanocarrier surface using "click chemistry" to improve the drug delivery efficiency to tumor tissues. The TP-NLC nanocarrier was thoroughly characterized with respect to its morphological attributes, photostability, tumor-targeting capabilities, ability to induce pyroptosis, reactive oxygen species (ROS)-responsive behavior, and anti-tumor efficacy both <i>in vitro</i> and <i>in vivo</i>. <b>Results:</b> GA encapsulated within the TP-NLC nanocarrier, induced pyroptosis in tumor cells, and enhanced the efficacy of ICG-induced pyroptosis under laser irradiation by disrupting intracellular antioxidant systems, realizing that the combination of GA and ICG synergistically induced caspase-3/GSDME-mediated pyroptosis in a ROS-dependent manner. Tumor cells of pyroptosis released cellular contents and tumor antigens, which subsequently promoted the maturation of dendritic cells (DCs), enhanced intratumoral infiltration of CD8⁺ T cells, initiated systemic antitumor immune response, and augmented the efficiency of PD-1 blockade against both primary and metastatic tumors. <b>Conclusion:</b> The combination of GA and ICG therapy utilizing the constructed nanocarriers presents an attractive therapeutic strategy to trigger pyroptosis and potentiate PD-1 blockade therapy for cervical cancer chemo-immunotherapy.