A NIR-II photothermal nanoplatform integrating intracellular Ca2+ elevation via TRPV1 activation for enhanced antitumor Therapy: A powerful combination of in situ tumor vaccination and vascular disruption

The treatment of triple-negative breast cancer (TNBC) remains a challenging issue in clinical settings due to the absence of effective therapeutic targets. Recent studies have revealed that transient receptor potential vanilloid type 1 (TRPV1), a non-selective Ca2+ channel responsive to noxious thermal stimuli, is frequently overexpressed in both malignant breast cancers and vascular cells, expected to be a promising therapeutic target. Herein, we developed a second near-infrared (NIR-II) photothermal nanoplatform named CT@hCuS to enhance immunotherapy and exacerbate tumor starvation, constructed from hollow CuS nanoparticles (hCuS) with tannic acid (TA) surface-coating and efficient Ca2+ loading via stable TA/Ca2+ complexation. The CT@hCuS platform releases Ca2+ in response to the mildly acidic pH of the tumor microenvironment. When exposed to intermittent 1064 nm laser irradiation, CT@hCuS delivers precise and controllable photothermy while avoiding potential adverse events of chemical TRPV1 agonists, activating TRPV1 and initiating an intracellular influx of Ca2+, which could not only destroy tumor vessels but also induce the immunogenic death of tumor cells. The resulting tumor antigens can be captured by CT@hCuS through binding with TA, leading to in situ tumor vaccination. Moreover, the nanoplatform via local administration contributes to durable drug release. Both in vitro and in vivo experiments demonstrated that CT@hCuS, combined with intermittent NIR-II laser irradiation, significantly enhanced the synergistic effects of intracellular Ca2+ elevation for tumor vaccination and tumor vascular disruption, which not only selectively block tumor nutrient sources but also transforms the immunosuppressive tumor environment into an immunoreactive phenotype for inhibiting TNBC growth and metastasis. This work presents a powerful NIR-II photothermal nanoplatform and proposes a unique synergistic strategy of immunotherapy and vascular disruption therapy for clinical TNBC treatment.