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Updated: Sep 19, 2025
Isolation of Primary Cancer-Associated Fibroblasts from a Syngeneic Murine Model of Breast Cancer for the Study of Targeted Nanoparticles
Published on: May 14, 2021
Artesunate Nanoplatform Targets the Serine-MAPK Axis in Cancer-Associated Fibroblasts to Reverse Photothermal
Dongdong Zheng1,2, Jiaqi Yan3,4,5, Xuejiao Liu6
1Department of Ultrasound, Fudan University Shanghai Cancer Center, Shanghai, 200032, P. R. China.
Abstract:
Cancer-associated fibroblasts (CAFs) play a pivotal role in inducing photothermal therapy (PTT) resistance of triple-negative breast cancer (TNBC), but with unclear mechanism. Herein, aminoethyl anisamide-modified nano-biomimetic low-density lipoprotein (A-aLDL) is used to target deliver the PTT agent and artesunate (ARS) to both CAFs and cancer cells. Though CAFs are sensitive to PTT and notably transition to heat-resistant phenotype, the formed protective barrier is destroyed by ARS. Subsequently, the outstanding anti-tumor effects are achieved through PTT in multiple models with such kind of combination therapy. Interestingly, the mechanism is discovered that serine metabolism plays a major role in CAF resistance through spatially omics. ARS disrupts serine homeostasis, thereby attenuating the cascade activity of GTPases in MAPK pathway. Meanwhile, MAP2K7 is the most potential target for sensitizing PTT. By integrating ARS with PTT agents, the serine-MAPK axis in CAFs is successfully modulated, thereby overcoming PTT resistance in TNBC therapy.
Insights
This study reveals how cancer-associated fibroblasts resist photothermal therapy in triple-negative breast cancer. Artesunate combined with photothermal therapy targets serine metabolism to overcome this resistance, enhancing anti-tumor effects.
Area of Science:
- Biomedical Engineering
- Oncology
- Nanomedicine
Background:
- Cancer-associated fibroblasts (CAFs) contribute to triple-negative breast cancer (TNBC) resistance to photothermal therapy (PTT).
- The precise mechanisms underlying CAF-mediated PTT resistance remain largely unelucidated.
- Targeted delivery strategies are needed to overcome PTT resistance in TNBC.
Purpose of the Study:
- To investigate the mechanism of CAF-mediated PTT resistance in TNBC.
- To develop a targeted combination therapy using artesunate (ARS) and PTT to overcome resistance.
- To identify key molecular targets for sensitizing CAFs to PTT.
Main Methods:
- Aminoethyl anisamide-modified nano-biomimetic low-density lipoprotein (A-aLDL) was synthesized for targeted delivery of PTT agents and ARS.
- Combination therapy of A-aLDL-delivered PTT agent and ARS was evaluated in TNBC models.
- Spatially resolved omics techniques were employed to investigate the underlying mechanisms of CAF resistance.
- The role of serine metabolism and the MAPK pathway in PTT resistance was analyzed.
Main Results:
- A-aLDL effectively delivered PTT agents and ARS to both CAFs and cancer cells.
- The combination therapy demonstrated significant anti-tumor effects by overcoming PTT resistance.
- Spatially omics revealed that serine metabolism is crucial for CAF resistance to PTT.
- ARS was found to disrupt serine homeostasis and attenuate MAPK pathway signaling, specifically targeting MAP2K7.
- Modulation of the serine-MAPK axis in CAFs sensitized them to PTT.
Conclusions:
- Targeted delivery of ARS and PTT agents via A-aLDL overcomes PTT resistance in TNBC by modulating the serine-MAPK axis in CAFs.
- Serine metabolism plays a critical role in CAF-mediated PTT resistance.
- ARS disrupts serine homeostasis, inhibiting the MAPK pathway and sensitizing CAFs to PTT, offering a promising therapeutic strategy for TNBC.
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