Black Phosphorus-Synergic Nitric Oxide Nanogasholder Spatiotemporally Regulates Tumor Microenvironments for Self-Amplifying Immunotherapy

Abstract

The lack of tumor immunogenicity coupled with the presence of tumor immunosuppression severely hinders antitumor immunity, especially in the treatment of "immune cold" tumors. Here, we have developed a drug-free and NIR-enabled nitric oxide (NO)-releasing nanogasholder (NO PS @BP) composed of an outer cloak of nitrate-containing polymeric NO donor and an inner core of black phosphorus (BP) as the energy converter to spatiotemporally regulate NO-mediated tumor microenvironment remodeling and achieve multimodal therapy. Following NIR-irradiation, BPinduced photothermia and its intrinsic reducing property accelerate NO release from the outer cloak, by which the instantaneous NO burst concomitant with mild photothermia, on the one hand, induces immunogenic cell death (ICD), thereby provoking antitumor responses such as the maturation of dendritic cells (DCs) and the infiltration of cytotoxic T lymphocytes (CTLs); on the other hand, it reverses tumor immunosuppression via Treg inhibition, M2 macrophage restraint, and PD-L1 downregulation, further strengthening antitumor immunity. Therefore, this drug-free NO PS @BP by means of multimodal therapy (NO gas therapy, immune therapy, photothermal therapy) realizes extremely significant curative effects against primary and distant tumors and even metastasis in B16F10 tumor models, providing a new modality to conquer immune cold tumors by NO-potentiated ICD and immunosuppression reversal.

Managing the immune microenvironment of osteosarcoma: the outlook for osteosarcoma treatment

“…34,[407][408][409] PTT mainly relies on a high local temperature to inhibit tumor cell proliferation, which can effectively eliminate cancer cells and enhance antitumor immune responses. [410][411][412] Moreover, PTT driven by nanoparticles has also been shown to induce effective treatment outcomes and is able to facilitate local heating of tumor tissues without impairing the surrounding normal tissue. 413 Additionally, PDT, as another noninvasive therapeutic approach, can also be activated by a laser of a specific wavelength, resulting in cytotoxic ROS accumulation in the presence of endogenous O 2 to eventually induce the death of tumor cells.…”

Research Progress of Nanomedicine-Based Mild Photothermal Therapy in Tumor

“…Similarly, Huang et al synthesized a drug-free nanoplatform (NO PS @BP) comprised of an outer cloak of nitrate-containing polymeric NO donor and an inner core of black phosphorus (BP, a PTA) to realize efficient multimodal therapy of mPTT, NO gas therapy, and ICB-based immunotherapy by taking advantage of the photothermal conversion function of BP as well as the dual function of NO which could induce ICD and interfere with PD-L1 activation. 233 Further, since the activation of immune response was a multistep cascade process, it was highly necessary to target multiple key steps in the cascade to promote a positive shift in the cancer-immunity cycle. 235 , 236 To this end, Feng et al adopted a strategy of sequential administration combined with mPTT to achieve the above objectives ( Figure 13b ).…”

“…Immunogenic cell death (ICD), as a major initiator of adaptive cascade immunity (TAAs release, DCs maturation, T cells activation, and TILs recruitment), is characterized by the exposure of TAAs with the release of damage-associated 231 Various methods of inducing ICD have been reported, including chemotherapy, radical-based therapy, gas therapy, and PTT. 187,232,233 Although these therapies have shown to activate immune responses by inducing ICD, the immune efficacy generated by the recruited TILs is largely compromised due to the presence of immune checkpoints such as programmed death ligand 1 (PD-L1) expressed on tumor cells, which interacts with programmed cell death 1 (PD-1) expressed on cytotoxic T lymphocytes (CTLs) and limits their function. 219,232 From this, continuously growing studies are inclined to combine ICD with ICB to improve antitumor immune efficacy.…”

Efficient tumor synergistic chemoimmunotherapy by self-augmented ROS-responsive immunomodulatory polymeric nanodrug

“…Immunogenic cell death (ICD) is a particular modality of cell death that can be induced by some specific chemotherapeutics such as doxorubicin (DOX), mitoxantrone (MIT) and paclitaxel (PTX) [5][6][7][8][9]. Cancer cells undergoing immunogenic cell death are characterized with the release of danger associated molecular patterns (DAMPs), such as calreticulin (CRT), adenosine triphosphate (ATP) and high mobility group box 1 (HMGB1), etc.…”