Chimeric antigen receptor T-cell (CAR-T) therapy has revolutionized the treatment of hematologic cancers and recently shown remarkable promise in autoimmune disorders such as systemic lupus erythematosus. Its success has inspired researchers to explore new horizons. Beyond oncology and immune-mediated diseases, CAR-T therapy is now being investigated for infectious diseases, fibrotic disorders, and aging-related conditions. While most of these applications are still in preclinical or early clinical stages, the future looks highly encouraging.
Infectious Diseases: Harnessing CAR-T to Combat Chronic Pathogens
By engineering T cells with receptors that recognize pathogen-derived antigens, CAR-T therapy can augment host immunity and potentially eradicate persistent infections. Early studies have focused on HIV, hepatitis B virus (HBV), and opportunistic fungal infections.
HIV Infection
- bNAb-derived CAR-T cells: Several groups have engineered CAR-T cells using recognition domains from broadly neutralizing antibodies (bNAbs) such as VRC01, 3BNC117, and 10-1074. In a phase I open-label trial (15 participants, 14 dosed), these CAR-T cells were well tolerated. Among patients who paused antiretroviral therapy, the median time to viral rebound extended to 5.3 weeks, with a measurable reduction in intact proviruses and viral RNA—evidence that the latent reservoir was under immune pressure.
- M10 CAR-T (Fudan University): A “triple-function” CAR-T approach combined with Chidamide stimulation activated latent HIV reservoirs and suppressed viral rebound. In a cohort of 18 HIV-1 patients, viral loads dropped by an average of 67%.
Chronic Hepatitis B (HBV)
- A14 CAR-T cells (2023, Virology): Designed to target the preS1 domain of the HBV surface protein, these CAR-T cells eradicated HBV-infected hepatocytes in humanized FRG mice, driving viral markers below detection limits and inducing antiviral cytokines.
- S-CAR (2019, Molecular Therapy): A fully human CAR targeting HBV envelope proteins showed selective clearance of infected cells and durable antiviral activity in preclinical models.
Invasive Fungal Infections
- Aspergillus fumigatus CAR-T: Researchers at University Hospital Würzburg engineered Af-CAR-T cells targeting conserved fungal hyphal epitopes. These cells not only killed A. fumigatus directly but also enhanced macrophage antifungal activity, demonstrating the feasibility of CAR-T for immunocompromised patients with invasive aspergillosis.
Fibrotic Diseases: Targeting Activated Fibroblasts
Fibrosis, driven by excessive collagen deposition, is a major cause of organ failure. CAR-T cells directed against fibroblast activation protein (FAP) or other fibroblast markers are emerging as powerful antifibrotic tools.
Cardiac Fibrosis
- FAP CAR-T (2019, Nature): Reduced cardiac fibrosis and restored function in murine models without off-target toxicity.
- In vivo CAR-T generation (2022, Science): Lipid nanoparticles encoding FAP CAR mRNA induced transient CAR-T activity in vivo, improving cardiac performance after injury.
- CD248-BBIR-T cells (2023, Nature Communications): This controllable, bispecific design eliminated late-activated fibroblasts in mature infarct scars, halting fibrosis progression and enhancing heart function.
Liver, Lung, and Kidney Fibrosis
- Liver (2025, Mount Sinai): LNP-mRNA delivered FAP CARs transiently, reducing hepatic fibrosis by modulating multiple cell types.
- Lung (2025, Shanghai Jiao Tong University): Transient CAR-T cells reversed bleomycin-induced pulmonary fibrosis, improving survival.
- Kidney (2025, Shandong University, Cell Stem Cell): CAR-T cells targeting PDGFRβ, a marker of ECM-producing cells, alleviated renal fibrosis in chronic kidney disease and showed efficacy in multi-organ fibrosis models.
Aging-Related Disorders: Senolytic CAR-T Therapy
Senescent cells, through their pro-inflammatory secretome (SASP), accelerate tissue degeneration and chronic disease. “Senolytic” CAR-T cells provide a targeted strategy for removing them.
- uPAR-CAR-T (2024, Nature Aging): Cleared senescent cells in aged and obese mice, improving glucose metabolism and physical performance.
- NKG2D-CAR-T (2024, Science Translational Medicine): Eliminated senescent cells in mice and aged nonhuman primates, mitigating age-related pathologies without adverse effects—an unprecedented proof of safety in higher mammals.
Other Novel Applications
Asthma
In 2024, Tsinghua University developed multifunctional “5TIF4” T cells for type-2 inflammation–driven asthma. A single infusion reduced eosinophilic lung inflammation, airway hyperreactivity, and asthma symptoms in murine models.
Alzheimer’s Disease
In 2024, Alzheimer’s & Dementia reported that CAR-T cells targeting colony-stimulating factor-1 receptor (CSF1R) curtailed microglial overactivation in AD-like mice. Treated animals showed improved cognition, reduced amyloid-β and tau pathology, and preserved synaptic proteins.
Conclusion
The versatility of CAR-T therapy is driving a paradigm shift well beyond oncology. From infectious and fibrotic diseases to aging and neurodegeneration, CAR-T offers a precision tool for durable immune modulation. Major challenges remain—cytokine release syndrome, neurotoxicity, and off-target effects—but advances in controllable CAR designs, transient expression systems, and rational patient selection promise to improve safety. Large-scale, multi-center clinical trials will be pivotal in determining whether these experimental successes can be translated into real-world therapies, marking the next chapter in the CAR-T revolution.
