Remodeling TME via feedback-driven photothermal-ferroptosis-immune cascade
Shengtao Wang1, Wenzheng Sun2, Jiyoung Yoo3
1Department of Pathology, Qilu Hospital of Shandong University, Jinan, 250012, China; Suzhou Institute for Advanced Research, University of Science and Technology of China, Suzhou, 215123, China.
Biomaterials
|July 4, 2026
Summary
This study introduces AIF nanoparticles for treating triple-negative breast cancer (TNBC). This novel therapy combines photothermal therapy (PTT) and ferroptosis, reprogramming the tumor microenvironment to enhance anti-cancer immunity and inhibit tumor growth.
Area of Science:
- Biomedical Engineering
- Nanotechnology
- Cancer Therapy
Background:
- Triple-negative breast cancer (TNBC) exhibits aggressive behavior and poor response to immunotherapy due to an immunosuppressive tumor microenvironment (TME).
- Current immunotherapies face challenges in overcoming the TME's resistance in TNBC.
- Developing novel therapeutic strategies is crucial for improving TNBC treatment outcomes.
Purpose of the Study:
- To develop a multifunctional nanoplatform (AIF NPs) integrating photothermal therapy (PTT), ferroptosis induction, and immunosuppressive axis blockade.
- To investigate the synergistic effects and feedback mechanisms within the AIF NPs therapeutic system.
- To evaluate the efficacy of AIF NPs in reprogramming the TNBC TME and enhancing anti-tumor immunity.
Main Methods:
- A silicon-based photothermal agent (IR1024) with high photothermal conversion efficiency was utilized for PTT.
- Ferroptosis was induced, leading to lipid peroxidation and downregulation of HSP90, enhancing sensitivity to PTT.
- The nanoplatform incorporated AB928 to block adenosine-mediated immunosuppression, promoting T cell infiltration and IFN-γ production.
Main Results:
- AIF NPs established a self-reinforcing loop of PTT, ferroptosis, and immunity, converting "cold" tumors to "hot" tumors.
- PTT-generated heat amplified ferroptosis, while ferroptosis enhanced thermo-sensitivity.
- The treatment resulted in over 90% tumor growth inhibition in a 4T1 murine model with minimal systemic toxicity.
Conclusions:
- The developed AIF NPs effectively overcome TNBC's immunosuppressive TME through a feedback-amplified therapeutic system.
- This strategy synergistically combines PTT, ferroptosis, and immune checkpoint blockade to enhance anti-tumor immunity.
- The findings present a promising approach for addressing therapeutic bottlenecks in aggressive breast cancer subtypes like TNBC.
