Tumor Vascular Destruction and cGAS‐STING Activation Induced by Single Drug‐Loaded Nano‐Micelles for Multiple Synergistic Therapies of Cancer

Abstract

Cancer and its metastasis/recurrence still threaten human health, despite various advanced treatments being employed. It is of great significance to develop simple drug formulations to enhance the efficacy and synergistic integration of various monotherapies. Herein, DMXAA, a vasodestructive agent with cGAS‐STING stimulation capacity, is integrated with polyethylene glycol grafted poly (lactic‐co‐glycolic) acid co‐polymer (PLGA‐PEG), obtaining PLGA‐PEG/DMXAA (PPD) nanoparticles to induce the tumor‐specific vascular destruction for multiple synergistic therapies of cancer. PPD could induce the formation of blood clots in the tumor after intravenous injection, which subsequently mediate photothermal therapy and further promote the release of oxygen for enhanced radiotherapy. Meanwhile, the enhanced vascular injury can induce perfect starvation therapy of tumor. More importantly, PPD‐mediated therapies could trigger potent systemic anti‐tumor immunity via inducing the immunogenic death of tumor cells and activating the cGAS‐STING pathway. Together with anti‐PD‐L1, PPD‐mediated therapies could not only remove the primary tumors, but also effectively eliminate the distant tumors, metastasis, and recurrence. Therefore, the modulation of tumor composition induced by a single drug‐loaded nano‐micelle could be utilized to enhance the therapeutic effect of multiple treatments for synergistic and systemic antitumor response, providing a practical strategy for cancer therapy.

Mn2+/CpG Oligodeoxynucleotides Codecorated Black Phosphorus Nanosheet Platform for Enhanced Antitumor Potency in Multimodal Therapy

“…As depicted in Figure e–h, the BPNS@Mn 2+ /CpG-based multimodal therapy has the potential to induce an increased populations of T EM cells (CD3 + CD8 + CD44 + CD62L – ) in lymph nodes and spleens, which can be further stimulated to generate cytotoxic T lymphocytes. This process effectively eradicates tumor metastasis and preventing recurrence. , …”

“…This process effectively eradicates tumor metastasis and preventing recurrence. 66,67 CONCLUSION Collectively, we have successfully developed a metal-ionmodified BPNS-based delivery/therapeutic nanoplatform (BPNS@Mn 2+ /CpG) for efficient codelivery of immunotherapeutic CpG ODNs and Mn 2+ into tumors, establishing a translational tumoricidal strategy for multimodal therapy (e.g., phototherapy and CDT), thereby achieving desired synergistic effects and potent antitumor efficacy. Importantly, the coordination of Mn 2+ on the BPNS surface significantly enhances its stability as well as its adsorption capacity for CpG ODNs.…”

“…The recurrence of solid tumors following medical treatment is a common phenomenon, which necessitates urgent attention to strategies for mitigating tumor recurrence in the field of oncology. ,, The aforementioned studies have demonstrated that BPNS@Mn 2+ /CpG-based multimodal therapy can induce potent antitumor immune responses in vivo . Therefore, we investigated whether the BPNS@Mn 2+ /CpG-based multimodal therapy could induce a long-lasting antitumor immune memory capable of inhibiting the growth of rechallenged homologous tumor cells in mice.…”

Differential reinforcement of cGAS-STING pathway-involved immunotherapy by biomineralized bacterial outer membrane-sensitized EBRT and RNT

“…More importantly, RT-damaged DNA fragments would leak into the cytoplasm from nucleus or mitochondria, further stimulating cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway [ 11 , 12 ]. The cGAS-STING activation shows powerful and positive effect on strengthening the T cells-mediated anti-tumor immunity and reversing M2 macrophage-mediated tumor immunosuppressive microenvironment by secreting type I interferon and various inflammatory cytokines [ 13 – 15 ]. Meanwhile, as the other side of a double-edged sword, RT up-regulates the expression of various immune checkpoint-related proteins, such as PD-L1, CTLA-4 and IDO-1, and decreases the number of lymphocytes in the body by causing severe bone marrow damage, negatively modulating the anti-tumor immunity [ 16 – 19 ].…”