A pro-death autophagy-based nanoplatform for enhancing antitumour efficacy with improved immune responses

by Selleckchem | Jan 20 2024

Due to the pro-survival effect of mild autophagy, the therapeutic effect of chemo-immunotherapy is unsatisfactory. In addition, the adverse tumour microenvironment (TME), including the lack of antigen presentation, the deficiency of oxygen supply and immunosuppressive cells, results in immune escape and metastasis. Herein, a novel nanoplatform (CS-3BP/PA@DOX) based on the autophagy cascade is proposed for the first time to deliver the chemotherapeutic doxorubicin (DOX) and respiration inhibitor 3-bromopyruvic acid (3BP) to overcome the above obstacles. CS-3BP/PA@DOX exerts a synergistic therapeutic effect to initiate pro-death autophagy and facilitate the antigen presentation process by combining DOX chemotherapy and starvation therapy with 3BP. Additionally, CS-3BP/PA@DOX remodelled the immunosuppressive TME by alleviating hypoxia, damaging dense ECM, and downregulating PD-L1 to enhance antitumour immunity. 3BP was found to promote GSH depletion by inhibiting respiration for the first time, which reduces the chemical resistance of cancer and increases the sensitivity of cells to ROS, providing a new therapeutic direction of 3BP for antitumour treatment. Collectively, this study offers an opportunity to magnify pro-death autophagy, augment antitumour efficacy, facilitate anti-metastatic effects, and boost immune responses.

Comments:

It sounds like the proposed nanoplatform, CS-3BP/PA@DOX, is designed to address several challenges in cancer treatment by leveraging the mechanisms of autophagy, chemotherapy, and immune modulation. This approach seems innovative in its attempt to tackle the complexities of the tumor microenvironment and enhance therapeutic outcomes.

The combination of doxorubicin (DOX) and 3-bromopyruvic acid (3BP) within the nanoplatform aims to trigger a synergistic effect by inducing pro-death autophagy and disrupting the tumor microenvironment. This strategy appears promising as it targets multiple aspects, such as:

1. **Enhancing Antigen Presentation:** By facilitating the antigen presentation process, the nanoplatform could potentially enhance the recognition of cancer cells by the immune system, aiding in immune-mediated destruction of tumors.

2. **Modifying Tumor Microenvironment:** Altering the immunosuppressive tumor microenvironment by reducing hypoxia, disrupting the extracellular matrix, and downregulating PD-L1 could promote an anti-tumor immune response.

3. **Enhancing Sensitivity to Treatment:** 3BP's ability to deplete GSH and increase sensitivity to reactive oxygen species (ROS) might reduce the chemical resistance of cancer cells, potentially making them more responsive to treatment.

This approach seems to offer a comprehensive strategy for addressing multiple aspects of cancer progression and resistance. The findings regarding the role of 3BP in promoting GSH depletion and altering cellular sensitivity to ROS could indeed pave the way for novel therapeutic directions in anti-tumor treatments.

If this research proves successful, it could significantly advance our understanding of cancer treatment by harnessing autophagy, chemotherapy, and immune modulation in a synergistic manner. It may offer a multifaceted approach to improving therapeutic efficacy while mitigating tumor resistance and metastasis.