Perylene-Mediated Cytoskeletal Dysfunction Remodels Cancer-Associated Fibroblasts to Augment Antitumor Immunotherapy

Area of Science:

• Biomedical Engineering
• Materials Science
• Cancer Therapy

Background:

• Cancer-associated fibroblasts (CAFs) promote tumor growth and immunosuppression.
• Reprogramming CAFs to a deactivated state is a key therapeutic challenge.
• The tumor microenvironment (TME) significantly impacts treatment efficacy.

Purpose of the Study:

• To develop a novel compound for targeted CAF reprogramming.
• To investigate the mechanism of CAF reprogramming via induced apoptosis and ROS.
• To evaluate the anti-tumor efficacy and immune modulation of the novel compound in vivo.

Main Methods:

• Synthesis of a perylene derivative (PDIC-OC).
• In vitro studies on CAFs to assess ROS generation, apoptosis, and TGF-β suppression.
• In vivo studies using B16F10 tumor-xenografted and lung-metastatic mouse models.
• Analysis of macrophage polarization, α-SMA levels, hypoxia, and T cell infiltration.

Main Results:

• PDIC-OC triggered endogenous ROS burst, leading to cytoskeletal dysfunction and apoptosis in CAFs.
• PDIC-OC suppressed TGF-β production, reprogrammed CAFs, and polarized M2 macrophages to M1.
• Significant reduction in tumor growth and lung metastasis was observed with PDIC-OC treatment.
• PDIC-OC alleviated tumor hypoxia and promoted cytotoxic T lymphocyte infiltration.

Conclusions:

• PDIC-OC offers a novel strategy for CAF-targeted cancer therapy by inducing apoptosis and suppressing TGF-β.
• The compound effectively reprograms the immunosuppressive TME, enhancing anti-tumor immunity.
• PDIC-OC demonstrates potent anti-tumor performance even at low concentrations, highlighting its therapeutic potential.