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Updated: Jun 10, 2026
Tumor Transplantation for Assessing the Dynamics of Tumor-Infiltrating CD8+ T Cells in Mice
Published on: June 12, 2021
VSIG4 suppresses antitumor T cell immunity via the SLC3A2-dependent metabolic-ionic checkpoint
Guoling Huang1,2,3, Ruirui He4,2,3,5, Wei Wang1,2,3
1The Key Laboratory for Human Disease Gene Study of Sichuan Province and the Department of Laboratory Medicine, Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China.
Abstract:
BackgroundImmune checkpoint blockade therapy aims to restore T-cell function within the tumor microenvironment (TME), eliciting durable antitumor responses. However, clinical response rates to PD-1/PD-L1 inhibitors remain limited, particularly in immunologically "cold" tumors such as pancreatic cancer, underscoring the need for alternative immunotherapeutic strategies. V-set and immunoglobulin domain-containing 4 (VSIG4) has been implicated in tumor progression, but its functional role in T-cell regulation and mechanisms of tumor immune evasion remain unclear.
Methods:
Syngeneic tumor models and human VSIG4 knock-in mice were employed to investigate the therapeutic effect of VSIG4 blockade. Mouse-specific and human-specific neutralizing antibodies against VSIG4 were administered across multiple tumor types, including pancreatic cancer. Tumor-infiltrating immune cells were analyzed by flow cytometry and functional assays. Mechanistic studies examined the interaction between VSIG4 and solute carrier family 3 member 2 (SLC3A2) and its impact on amino acid transport, ion flux, and T-cell activation.
Results:
Therapeutic blockade of VSIG4 significantly suppressed tumor growth and prolonged survival in several cancer models, with particular efficacy in pancreatic cancer. VSIG4 expression correlated with tumor aggressiveness, and its blockade reactivated CD8+ T cells within the TME, enhancing intratumoral infiltration and effector function. Mechanistically, VSIG4 directly bound to SLC3A2, a chaperone for amino acid transporters, thereby impairing glutamine uptake, disrupting sodium and calcium flux, and ultimately suppressing T-cell activation. VSIG4 blockade restored nutrient and ion availability to CD8+ T cells, thereby reinvigorating antitumor immunity.
Conclusions:
These findings define a previously unrecognized metabolic-ionic checkpoint axis by which VSIG4 restricts T-cell activation through SLC3A2. Blockade of VSIG4 reprograms the TME and enhances antitumor immunity, highlighting VSIG4 as a promising therapeutic target, particularly in metabolically repressive tumors such as pancreatic cancer.
Insights
Blocking V-set and immunoglobulin domain-containing 4 (VSIG4) reactivates CD8+ T cells by restoring nutrient and ion balance, significantly suppressing tumor growth, especially in pancreatic cancer. This reveals a new metabolic-ionic checkpoint for immunotherapy.
Area of Science:
- Immunology
- Cancer Biology
- Metabolic Pathways
Background:
- Immune checkpoint blockade therapy aims to enhance T-cell function against tumors.
- Limited response rates to PD-1/PD-L1 inhibitors, especially in "cold" tumors like pancreatic cancer, necessitate novel strategies.
- V-set and immunoglobulin domain-containing 4 (VSIG4) is implicated in tumor progression, but its role in T-cell regulation and immune evasion is unclear.
Purpose of the Study:
- To investigate the therapeutic potential of blocking V-set and immunoglobulin domain-containing 4 (VSIG4) in cancer.
- To elucidate the mechanisms by which VSIG4 influences T-cell function and tumor immune evasion.
- To evaluate VSIG4 blockade as a strategy, particularly for pancreatic cancer.
Main Methods:
- Utilized syngeneic tumor models and human VSIG4 knock-in mice.
- Administered neutralizing antibodies against VSIG4 in various tumor types, including pancreatic cancer.
- Analyzed tumor-infiltrating immune cells and investigated the VSIG4-SLC3A2 interaction's impact on nutrient/ion transport and T-cell activation.
Main Results:
- VSIG4 blockade significantly inhibited tumor growth and improved survival across multiple models, notably in pancreatic cancer.
- VSIG4 expression correlated with tumor aggressiveness; blockade reactivated CD8+ T cells, enhancing their infiltration and function.
- VSIG4 binds SLC3A2, impairing glutamine uptake and ion flux, thus suppressing T-cell activation. Blockade restored these functions.
Conclusions:
- VSIG4 acts as a metabolic-ionic checkpoint, inhibiting T-cell activation via SLC3A2.
- VSIG4 blockade reprograms the tumor microenvironment, boosting antitumor immunity.
- VSIG4 is a promising therapeutic target, especially for metabolically challenging tumors like pancreatic cancer.
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