Clinical bottom line
Chimeric antigen receptor natural killer (CAR NK) cell therapies represent a promising emerging modality for treating hematologic malignancies, with potential advantages over CAR T-cell therapies in safety and off-the-shelf availability. However, infectious complications remain a significant concern due to underlying immunosuppression, lymphodepleting conditioning regimens, and therapy-related immune modulation. Current evidence highlights the need for vigilant infection surveillance, prophylaxis tailored to the unique immunologic milieu, and multidisciplinary management strategies. While CAR NK therapies may reduce some risks seen with CAR T cells, such as cytokine release syndrome, infectious risks are incompletely characterized and warrant ongoing study to optimize clinical management.
What the evidence shows
CAR NK cell therapies are engineered to target hematologic cancers by harnessing innate immune cytotoxicity with improved safety profiles compared to CAR T cells, including lower rates of cytokine release syndrome and neurotoxicity (Xu et al., 2019; Kumar et al., 2024). Preclinical and early clinical studies demonstrate encouraging anti-tumor efficacy in acute myeloid leukemia, lymphomas, and T/NK cell malignancies (Li et al., 2022; Kumar et al., 2024).
Infections remain a major cause of morbidity and mortality in patients undergoing cellular therapies for hematologic malignancies, largely driven by profound immunosuppression from prior chemotherapy, lymphodepleting regimens, and disease-related immune dysfunction (Kahraman et al., 2021). Although CAR NK therapies may require less intensive conditioning than CAR T cells, patients still experience neutropenia, mucosal barrier injury, and impaired cellular immunity that predispose to bacterial, viral, and fungal infections (Liu et al., 2026).
Limited clinical data specifically on infectious complications post-CAR NK therapy indicate a spectrum of infections similar to other cellular therapies, including bloodstream infections, viral reactivations (e.g., CMV, EBV), and invasive fungal infections (Kumar et al., 2024; Liu et al., 2026). The off-the-shelf nature of many CAR NK products may reduce delays and allow earlier intervention, but also raises concerns about allogeneic immune reactions and graft-versus-host-like effects that could further compromise host defenses (Al-khreisat et al., 2026).
Strategies to mitigate infection risk include preemptive antimicrobial prophylaxis, close monitoring for viral reactivation, and individualized immunosuppressive regimens balancing graft persistence with infection susceptibility (Al-khreisat et al., 2026; Kumar et al., 2024). Combination approaches integrating CAR NK cells with checkpoint inhibitors or cytokine support are under investigation but may alter infection risk profiles (Zhou et al., 2024).
Caveats and uncertainty
The evidence base for infectious complications in CAR NK therapy remains limited by small patient cohorts, heterogeneity in malignancy types, conditioning regimens, and CAR constructs (Li et al., 2022; Liu et al., 2026). Most data derive from early-phase trials or preclinical models, limiting generalizability to broader clinical practice. Long-term infectious outcomes and optimal prophylaxis strategies have not been established.
Comparisons with CAR T-cell therapies are complicated by differences in patient selection and treatment protocols. The immunologic impact of CAR NK cells, including effects on endogenous immune reconstitution and susceptibility to opportunistic infections, requires further elucidation. Additionally, the potential for off-target effects or immune-mediated toxicities influencing infection risk remains under investigation (Al-khreisat et al., 2026).
How this may change practice
Clinicians managing patients receiving CAR NK therapies should anticipate infectious risks similar to other cellular therapies but remain alert to potentially distinct patterns due to differences in immune modulation and conditioning intensity. Early identification and management of infections through multidisciplinary collaboration with infectious disease specialists are critical.
Infection prevention protocols should be adapted to incorporate emerging data on CAR NK-specific risks, including tailored antimicrobial prophylaxis and vigilant viral monitoring. As CAR NK therapies become more widely available, standardized guidelines for infection surveillance and management will be essential.
Ongoing clinical trials and real-world registries will inform best practices, including the impact of combination therapies and novel CAR NK constructs on infection risk. Ultimately, integrating infectious disease expertise into CAR NK therapy programs will optimize patient outcomes and safety.