Nanotherapeutics targeting autophagy regulation for improved cancer therapy.

The clinical efficacy of current cancer therapies falls short, and there is a pressing demand to integrate new targets with conventional therapies. Autophagy, a highly conserved self-degradation process, has received considerable attention as an emerging therapeutic target for cancer. With the rapid development of nanomedicine, nanomaterials have been widely utilized in cancer therapy due to their unrivaled delivery performance. Hence, considering the potential benefits of integrating autophagy and nanotechnology in cancer therapy, we outline the latest advances in autophagy-based nanotherapeutics. Based on a brief background related to autophagy and nanotherapeutics and their impact on tumor progression, the feasibility of autophagy-based nanotherapeutics for cancer treatment is demonstrated. Further, emerging nanotherapeutics developed to modulate autophagy are reviewed from the perspective of cell signaling pathways, including modulation of the mammalian target of rapamycin (mTOR) pathway, autophagy-related (ATG) and its complex expression, reactive oxygen species (ROS) and mitophagy, interference with autophagosome-lysosome fusion, and inhibition of hypoxia-mediated autophagy. In addition, combination therapies in which nano-autophagy modulation is combined with chemotherapy, phototherapy, and immunotherapy are also described. Finally, the prospects and challenges of autophagy-based nanotherapeutics for efficient cancer treatment are envisioned.

P2X7-Mediated Antigen-Independent Activation of CD8+ T Cells Promotes Salt-Sensitive Hypertension.

BACKGROUND: CD8+ T cells (CD8Ts) have been implicated in hypertension. However, the specific mechanisms are not fully understood. In this study, we explore the contribution of the P2X7 (purinergic receptor P2X7) receptor to CD8T activation and subsequent promotion of sodium retention in the kidney. METHODS: We used mouse models of hypertension. Wild type were used as genetic controls, OT1 and Rag2/OT1 mice were utilized to determine antigen dependency, and P2X7-knockout mice were studied to define the role of P2X7 in activating CD8Ts and promoting hypertension. Blood pressure was monitored continuously and kidneys were obtained at different experimental end points. Freshly isolated CD8Ts from mice for activation assays and ATP stimulation. CD8T activation-induced promotion of sodium retention was explored in cocultures of CD8Ts and mouse DCTs. RESULTS: We found that OT1 and Rag2/OT1 mice, which are nonresponsive to common antigens, still developed hypertension and CD8T-activation in response to deoxycorticosterone acetate/salt treatment, similar to wild-type mice. Further studies identified the P2X7 receptor on CD8Ts as a possible mediator of this antigen-independent activation of CD8Ts in hypertension. Knockout of the P2X7 receptor prevented calcium influx and cytokine production in CD8Ts. This finding was associated with reduced CD8T-DCT stimulation, reversal of excessive salt retention in DCTs, and attenuated development of salt-sensitive hypertension. CONCLUSIONS: Our findings suggest a novel mechanism by which CD8Ts are activated in hypertension to exacerbate salt retention and infer that the P2X7 receptor on CD8Ts may represent a new therapeutic target to attenuate T-cell-mediated immunopathology in hypertension.

Nanomaterial-mediated modulation of the cGAS-STING signaling pathway for enhanced cancer immunotherapy.

Despite the current promise of immunotherapy, many cancer patients still suffer from challenges such as poor immune response rates, resulting in unsatisfactory clinical efficacy of existing therapies. There is an urgent need to combine emerging biomedical discoveries and innovations in traditional therapies. Modulation of the cGAS-STING signalling pathway represents an important innate immunotherapy pathway that serves as a crucial DNA sensing mechanism in innate immunity and viral defense. It has attracted increasing attention as an emerging target for cancer therapy. The recent advancements in nanotechnology have led to the significant utilization of nanomaterials in cancer immunotherapy, owing to their exceptional physicochemical properties such as large specific surface area and efficient permeability. Given the rapid development of cancer immunotherapy driven by the cGAS-STING activation, this study reviews the latest research progress in employing nanomaterials to modulate this signaling pathway. Based on the introduction of the main activation mechanisms of cGAS-STING pathway, this review focuses on nanomaterials that mediate the agonists involved and effectively activate this signaling pathway. In addition, combination nanotherapeutics based on the activation of the cGAS-STING signaling pathway are also discussed, including emerging strategies combining nanoformulated agonists with chemotherapy, radiotherapy as well as other immunomodulation in tumor targeting therapy. STATEMENT OF SIGNIFICANCE: Given the rapid development of cancer immunotherapy driven by the cGAS / STING activation, this study reviews the latest research advances in the use of nanomaterials to modulate this signaling pathway. Based on the introduction of key cGAS-STING components and their activation mechanisms, this review focuses on nanomaterials that can mediate the corresponding agonists and effectively activate this signaling pathway. In addition, combination nanotherapies based on the activation of the cGAS-STING signaling pathway are also discussed, including emerging strategies combining nanoformulated agonists with chemotherapy, radiotherapy as well as immunomodulation in cancer therapy,.