Dual-Epigenetically Relieving the MYC-Correlated Immunosuppression via an Advanced Nano-Radiosensitizer Potentiates Cancer Immuno-Radiotherapy.

Cancer cells can upregulate the MYC expression to repair the radiotherapy-triggered DNA damage, aggravating therapeutic resistance and tumor immunosuppression. Epigenetic treatment targeting the MYC-transcriptional abnormality may intensively solve this clinical problem. Herein, 5-Aza (a DNA methyltransferase inhibitor) and ITF-2357 (a histone deacetylase inhibitor) are engineered into a tungsten-based nano-radiosensitizer (PWAI), to suppress MYC rising and awaken robust radiotherapeutic antitumor immunity. Individual 5-Aza depletes MYC expression but cannot efficiently awaken radiotherapeutic immunity. This drawback can be overcome by the addition of ITF-2357, which triggers cancer cellular type I interferon (IFN-I) signaling. Coupling 5-Aza with ITF-2357 ensures that PWAI does not evoke the treated model with high MYC-related immune resistance while amplifying the radiotherapeutic tumor killing, and more importantly promotes the generation of IFN-I signal-related proteins involving IFN-α and IFN-ß. Unlike the radiation treatment alone, PWAI-triggered immuno-radiotherapy remarkably enhances antitumor immune responses involving the tumor antigen presentation by dendritic cells, and improves intratumoral recruitment of cytotoxic T lymphocytes and their memory-phenotype formation in 4T1 tumor-bearing mice. Downgrading the radiotherapy-induced MYC overexpression via the dual-epigenetic reprogramming strategy may elicit a robust immuno-radiotherapy.

PhotoPyro-Induced cGAS-STING Pathway Activation Enhanced Anti-Melanoma Immunotherapy via a Manganese-Coordinated Nanomedicine.

Malignant melanoma is an aggressive skin cancer with a high metastatic and mortality rate. Owing to genetic alterations, melanoma cells are resistant to apoptosis induction, which reduces the efficacy of most adjuvant systemic anticancer treatments in clinical. Here, a noninvasive strategy for anti-melanoma immunotherapy based on a manganese-coordinated nanomedicine is provided. Supplemented with photoirradiation, photon-mediated reactive oxygen species generation by photosensitizer chlorin e6 initiates photon-controlled pyroptosis activation (PhotoPyro) and promotes antitumor immunity. Simultaneously, photoirradiation-triggered double-stranded DNA generation in the cytosol would activate the Mn2+ -sensitized cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway, which further augment the PhotoPyro-induced immune response. The syngeneic effect of these immunostimulatory pathways significantly benefits dendritic cell maturation by damage-associated molecular patterns and proinflammatory cytokines secretion, thereby activating T cells and remarkably eliciting a systemic antitumor immune response to inhibiting both primary and distant tumor growth. Collaboratively, the photoirradiation-triggered PhotoPyro and cGAS-STING pathway activation by nanomedicine administration could enhance the antitumor capacity of immunotherapy and serve as a promising strategy for melanoma treatment.

Gel/hydrogel-based in situ biomaterial platforms for cancer postoperative treatment and recovery.

Tumor surgical resection is the major strategy for cancer treatment. Meanwhile, perioperative treatment especially the postoperative adjuvant anticancer strategies play essential roles in satisfying therapeutic results and rapid recovery. Postoperative tumor recurrence, metastasis, bleeding, inter-tissue adhesion, infection, and delayed wound healing are vital risks that could lead to poor prognosis or even treatment failure. Therefore, methods targeting these postoperative complications are in desperate need. In situ biomaterial-based drug delivery platforms are promising candidates for postoperative treatment and recovery, resulting from their excellent properties including good biocompatibility, adaptive shape, limited systemic effect, designable function, and easy drug loading. In this review, we focus on introducing the gel/hydrogel-based in situ biomaterial platforms involving their properties, advantages, and synthesis procedures. Based on the loaded contents in the gel/hydrogel such as anticancer drugs, immunologic agents, cell components, and multifunctional nanoparticles, we further discuss the applications of the in situ platforms for postoperative tumor recurrence and metastasis inhibition. Finally, other functions aiming at fast postoperative recovery were introduced, including hemostasis, antibacterial infection, adhesion prevention, tissue repair, and wound healing. In conclusion, gel/hydrogel is a developing and promising platform for postoperative treatment, exhibiting gratifying therapeutic effects and inconspicuous toxicity to normal tissues, which deserves further research and exploration.

Activation of FGFR2 Signaling Suppresses BRCA1 and Drives Triple-Negative Mammary Tumorigenesis That is Sensitive to Immunotherapy.

Fibroblast growth factor receptor 2 (FGFR2) is a membrane-spanning tyrosine kinase that mediates FGF signaling. Various FGFR2 alterations are detected in breast cancer, yet it remains unclear if activation of FGFR2 signaling initiates tumor formation. In an attempt to answer this question, a mouse model berrying an activation mutation of FGFR2 (FGFR2-S252W) in the mammary gland is generated. It is found that FGF/FGFR2 signaling drives the development of triple-negative breast cancer accompanied by epithelial-mesenchymal transition that is regulated by FGFR2-STAT3 signaling. It is demonstrated that FGFR2 suppresses BRCA1 via the ERK-YY1 axis and promotes tumor progression. BRCA1 knockout in the mammary gland of the FGFR2-S252W mice significantly accelerated tumorigenesis. It is also shown that FGFR2 positively regulates PD-L1 and that a combination of FGFR2 inhibition and immune checkpoint blockade kills cancer cells. These data suggest that the mouse models mimic human breast cancers and can be used to identify actionable therapeutic targets.