The core principle of a chimeric antigen receptor is elegant: a synthetic receptor is built by fusing an antibody-derived recognition domain to the intracellular signaling machinery of the T-cell receptor. When the recognition domain binds its target antigen on a cell surface, the signaling domains activate the T cell, triggering killing of the target cell, proliferation and cytokine release. In cancer, this has produced dramatic remissions in patients with relapsed leukemias and lymphomas. In infection, the theoretical appeal is equally strong. Chronic pathogens such as HIV, hepatitis B virus, Epstein-Barr virus and cytomegalovirus establish reservoirs inside host cells that evade or exhaust the natural immune response, and conventional antimicrobial drugs often cannot reach or eliminate these sanctuaries. An engineered T cell, in principle, could seek out infected cells wherever they hide.

The review identifies three distinct recognition classes that have emerged in the field. The first targets pathogen surface structures, molecules displayed directly by the infectious agent itself. The second targets infected-cell surface antigens, host or viral proteins that appear on the membrane of a cell once it has been hijacked. The third and most sophisticated class targets pathogen-derived peptide-human leukocyte antigen complexes, in which fragments of microbial proteins are presented on the cell surface by HLA molecules, mimicking the way natural T cells recognize infection. Each class carries distinct trade-offs in specificity, coverage and safety, and the choice among them shapes everything downstream, from receptor affinity tuning to the risk of off-tumor, off-infection tissue damage.

HIV provides the most mature clinical evidence base. Because the virus infects and ultimately depletes the very CD4 T cells that a CAR approach would deploy, researchers have had to engineer HIV-specific CARs into cells resistant to infection, and early clinical studies have demonstrated that such products can persist long-term in patients. Encouragingly, trials have recorded reductions in reservoir-associated markers, suggesting that engineered cells can reach and engage the latent viral reservoir that antiretroviral therapy suppresses but never eradicates. The critical limitation, however, is equally clear: no study has yet achieved reproducible control of HIV without ongoing antiretroviral therapy. The engineered cells persist and function, but they have not yet delivered a functional cure, and the review is careful to frame current results as proof of biological feasibility rather than therapeutic victory.

The hepatitis viruses illustrate a different set of challenges. Studies of CAR-T cells directed against hepatitis B virus, including targets such as the hepatitis B surface antigen, have shown that engineered cells can recognize and eliminate infected hepatocytes. But the liver is an unforgiving arena. Eliminating infected hepatocytes en masse risks hepatic injury in organs already compromised by chronic inflammation and, in some patients, by hepatocellular carcinoma. Epstein-Barr virus and cytomegalovirus programs have produced evidence that infected cells can be recognized, but they have also exposed two recurring problems: antigen expression on infected cells is variable and often heterogeneous, meaning that cells with low or absent target levels escape killing, and infected cells can actively resist lysis through immune-evasion mechanisms honed over long co-evolution with their hosts.

Perhaps the most surprising frontier is fungal infection. The review describes preclinical CAR-T cells engineered to recognize fungal cell wall components, including β-glucan, hyphal antigens, glucuronoxylomannan, the capsular polysaccharide of Cryptococcus, and mannan. These constructs have shown activity against fungal pathogens in laboratory and animal models, opening a genuinely novel therapeutic category for invasive fungal disease, which carries high mortality in immunocompromised patients and is increasingly threatened by antifungal drug resistance. Bacterial targets, by contrast, remain largely untouched. Direct antibacterial CAR-T evidence is minimal, and the reason is fundamental rather than technical: bacterial clearance in the body depends heavily on phagocytes and the complement system, effector mechanisms that a cytotoxic T cell does not replicate. A CAR-T cell is optimized to kill host cells, not to engulf or opsonize extracellular bacteria.

Across all pathogens, the review catalogs a shared set of constraints that repeatedly blunt efficacy. Antigens may be dynamic, appearing and disappearing as infection cycles progress, or soluble, circulating in the blood and acting as decoys that exhaust engineered cells before they reach their targets. Tissue reservoirs, particularly in sanctuary sites with poor T-cell trafficking, remain hard to reach. The patient’s own T cells, the raw material for manufacturing, are often impaired by the very infection being treated, yielding products with poor fitness. Manufacturing delay is another critical variable: acute infections move on a timescale of days, while autologous cell production takes weeks, demanding either allogeneic off-the-shelf platforms or infections with a stable, chronic treatment window. Finally, organ-specific inflammation in infected tissues amplifies the risk of cytokine release syndrome and collateral damage.

The engineering response to these problems is already substantial. Multispecific receptors that recognize several antigens simultaneously can counter antigen escape. Transient or switchable receptor designs, in which CAR expression or activity can be controlled with an administered drug, offer a dose-control mechanism that oncology CAR-T lacks. Safety switches allow engineered cells to be eliminated if toxicity escalates. Local delivery, depositing cells directly into infected tissue such as the liver or the central nervous system, may bypass trafficking barriers. Checkpoint modulation, blocking inhibitory pathways such as PD-1 and PD-L1, can rescue exhausted products, while cytokine-armored designs engineer cells to secrete supportive factors like interleukins or interferon-γ that sustain their own function in hostile tissue. Longitudinal blood-based monitoring, tracking engineered cell persistence and reservoir markers over time, is proposed as the framework for measuring whether any of these interventions actually works.

The review’s most consequential contribution may be its prioritization framework. Rather than chasing every pathogen, the authors argue that development should concentrate on infections with stable target exposure, a treatment window compatible with cell delivery timelines, measurable microbiological endpoints that can demonstrate effect in trials, and a tolerable consequence of eliminating infected cells. That last criterion is the subtlest: in cancer, destroying the target cell is the goal, but in chronic hepatitis B, for example, every infected hepatocyte killed is liver tissue lost, so the therapeutic index depends on the liver’s capacity to regenerate and on how precisely the receptor discriminates infected from healthy cells. Clinical progress, the authors conclude, will depend on matching the engineered effector mechanism to pathogen biology, tissue location and host immune status, a discipline-specific calibration that no oncology playbook can provide.

What emerges from the analysis is a field at an inflection point. The biology has been proven in principle: engineered cells can persist in patients, traffic to infected tissues, engage viral reservoirs and reduce disease-associated markers. The engineering toolkit for safety, control and multi-target recognition is maturing rapidly, and preclinical fungal programs suggest the concept extends beyond viruses. Yet the distance between reservoir-marker reduction and therapy-free control remains wide, and the review is explicit that every proposed improvement, from switchable receptors to armored cytokines, requires infection-specific validation rather than extrapolation from cancer data. If that validation succeeds, the coming years could see cellular immunotherapy expand from the oncology ward into infectious disease units, offering a precision weapon against pathogens that have so far outlasted every drug aimed at them.

Subject of Research: CAR-T-cell immunotherapy for infectious diseases

Article Title: CAR-T-cell therapy for infectious diseases: from concept to clinic

Article References: Su, S., Zhou, M., Chen, L., Zhu, X., & Xiao, Y. (2026). CAR-T-cell therapy for infectious diseases: from concept to clinic. Journal of Translational Medicine. https://doi.org/10.1186/s12967-026-08906-4

Image Credits: AI Generated

DOI: 10.1186/s12967-026-08906-4

Keywords: CAR-T-cell therapy, infectious diseases, HIV, hepatitis B virus, Epstein-Barr virus, cytomegalovirus, fungal infection, antimicrobial immunity, cellular therapy, target antigens, chimeric antigen receptor, immunotherapy