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Decoding the immunometabolic landscape identifies SLC7A5 as a vulnerability in chemo-immunotherapy resistant TNBC
Sen Zhong1, Bolin Yu1, Shengyi Zhou1
1School of Medicine, Department of Breast and Thyroid Surgery, Tongji University, Shanghai Tenth People's Hospital, 301 Yanchang Middle Road, 200072, Shanghai, China.
Clinical and Experimental Medicine
|June 25, 2026
Summary
Triple-negative breast cancer (TNBC) is resistant to chemo-immunotherapy due to metabolic reprogramming. Blocking the kynurenine-SLC7A5 axis restores T cell function and enhances treatment efficacy.
Area of Science:
- Oncology
- Metabolic pathways
- Immunology
Background:
- Metabolic reprogramming in the tumor microenvironment (TME) hinders chemo-immunotherapy for triple-negative breast cancer (TNBC).
- Intercellular metabolic crosstalk driving immune evasion in TNBC is not fully understood.
- Single-cell metabolic atlases are needed to identify TNBC vulnerabilities.
Purpose of the Study:
- To create a single-cell metabolic atlas of the TNBC ecosystem.
- To decode spatial and cell-type-specific metabolic vulnerabilities.
- To identify metabolic crosstalk driving immune evasion in TNBC.
Main Methods:
- Multidimensional single-cell analysis of the TNBC ecosystem.
- In vitro co-culture and in vivo TNBC models.
- Pharmacological blockade of the amino acid transporter SLC7A5 using JPH203.
Main Results:
- Identified a paracrine metabolic axis: CXCL9+ macrophages produce kynurenine, imported by cytotoxic T cells.
- Kynurenine uptake impairs T cell effector function and causes exhaustion.
- SLC7A5 inhibition (JPH203) restored T cell function and improved chemo-immunotherapy efficacy.
Conclusions:
- The Kynurenine-SLC7A5 axis is a key driver of immunosuppression in TNBC.
- Targeting amino acid transport offers a strategy to overcome chemo-immunotherapy resistance.
- Pharmacological blockade of SLC7A5 enhances anti-tumor immunity in TNBC.
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