Cocktail strategy-based nanomedicine: A synergistic cascade of starvation, NIR-II photothermal, and gas therapy for enhanced tumor immunotherapy.

Immunotherapy has emerged as a highly promising strategy in the realm of cancer treatment, wherein immunogenic cell death (ICD) is considered a potential trigger for anti-tumor immunity by inducing adaptive immunity to dying cell antigens. This process is often accompanied by the exposure, active secretion, or passive release of a large number of damage-associated molecular patterns (DAMPs), which activate dendritic cells (DCs) and enhance their antigen-presenting capacity. Subsequently, it promotes the recruitment and activation of cytotoxic T lymphocytes, ultimately leading to tumor growth inhibition. In addition, polarizing the M2 phenotype of tumor-associated macrophages (TAMs) to the M1 phenotype is another way to activate anti-tumor immunity, which can further enhance the effect of anti-tumor immunotherapy. In this study, we engineered a composite nanoparticle of UiO-66-NH@Gold nanoshells@GOx-P-Arg (denoted as UGsGP). The gold nano shells in UGsGP exhibit a broad Near-Infrared-II (NIR-II) absorption to give a high photothermal conversion efficiency and achieve photothermal therapy (PTT). The GOx in UGsGP involves the breakdown of glucose, which results in a decrease in ATP levels and an inhibition of HSP90 and HSP70 production, ultimately enhancing the heat sensitivity of the tumor for PTT. In addition, GOx-mediated starvation therapy by glucose exhaustion produces a substantial amount of hydrogen peroxide (HO), which can then react with P-Arg to produce intratumoral NO Thus, the synergistic effect of PTT resensitization, the photothermally-enhanced GOx-mediated starvation, and NO-based gas therapy promote the induction of ICD and the polarization of TAMs. The combination therapy exhibits significant antitumor effects both in vitro and in vivo. STATEMENT OF SIGNIFICANCE: (1) Gold nanoshells on the surface of UiO-66-NH display a broad absorption spectrum ranging from 900 to 1700 nm, combined with a high photothermal conversion efficiency of 74.0 %, demonstrating their remarkable ability to harness and convert light energy into heat for effective tumor ablation. (2) Under laser irradiation, GOx within the UGsGPs effectively consumes glucose, increasing intratumoral HO levels, which then reacts with P-Arg to produce NO within the tumor. Concurrently, the reduction in ATP levels suppresses HSP90 and HSP70 production, thereby enhancing the tumor's sensitivity to photothermal therapy. (3) The synergistic combination of NO gas therapy, starvation therapy, and PTT promotes ICD induction and TAM polarization, thereby improving the therapeutic outcomes for primary and distant tumors.