The scale of the problem is enormous. According to GLOBOCAN 2022 estimates from the International Agency for Research on Cancer, roughly 20 million new cancer cases occur worldwide each year, and solid tumors account for more than 90 percent of them. Lung, breast, colorectal, prostate, and gastric cancers alone make up 45.8 percent of global incidence. Immune checkpoint inhibitors have delivered durable responses in selected solid tumors, while CAR-T therapy remains largely investigational outside blood cancers. Against this backdrop, NK cell-based immunotherapy has attracted attention for its widely recognized low-risk profile and its potential as an off-the-shelf product.

But solid tumor patients are not the same population as hematologic cancer patients. They tend to be older, with lung and gastrointestinal tumors typically appearing at 60 to 70 years of age, and they carry a heavier burden of cardiovascular comorbidities, including hypertension in 26.0 percent, coronary heart disease in 7.8 percent, and heart failure in 3.3 percent. Prior anthracycline chemotherapy or thoracic radiotherapy often leaves the myocardium in a pre-injured state. Because immune checkpoint inhibitors and CAR-T cells can both trigger cardiovascular toxicity through mechanisms such as cytokine release syndrome, the authors argue that as NK cell strategies expand into solid tumors, their cardiac safety must be comprehensively evaluated before clinical translation proceeds.

NK cells kill through a coordinated set of molecular pathways. The activating receptor NKG2D binds stress-induced ligands such as MICA/B and ULBPs on tumor cells, natural cytotoxicity receptors NKp30, NKp44, and NKp46 recognize tumor-specific antigens, and CD16 mediates antibody-dependent cellular cytotoxicity. Once activated, NK cells release perforin and granzymes to punch pores in target-cell membranes, or trigger apoptosis through death ligands such as FasL and TRAIL. They also secrete interferon-gamma and tumor necrosis factor-alpha to recruit dendritic cells and T cells. Crucially, inhibitory receptors such as KIR and NKG2A recognize MHC class I molecules on healthy tissue, generating tolerance and limiting autoimmune injury.

The tumor microenvironment, however, systematically disarms this arsenal. High concentrations of TGF-beta and IDO suppress NK cell activation and proliferation, while nutrient deprivation, hypoxia, and metabolic byproducts such as lactate and adenosine further erode cytotoxic function. Upregulation of HIF-1alpha in solid tumors induces mitochondrial dysfunction in NK cells and inhibits aerobic glycolysis, causing energy-metabolism failure. Tumor-infiltrating NK cells also upregulate inhibitory checkpoints including PD-1, TIM-3, LAG-3, and TIGIT. Single-cell atlases of breast cancer and hepatocellular carcinoma have identified exhausted NK subsets with high expression of NR4A family genes and KLRC1, and these patients tend to have poorer prognoses.

Three therapeutic strategies aim to reverse this exhaustion. Genetic engineering, most notably chimeric antigen receptor NK cells (CAR-NK), equips NK cells with tumor-antigen-specific receptors; genome-wide CRISPR screening has identified negative regulators such as MED12, ARIH2, and CCNC whose knockout enhances metabolic adaptability, and chemokine receptors such as CXCR4 can be introduced to improve tumor infiltration. Antibody-mediated approaches, including bispecific and trispecific immune-cell engagers that bridge tumor antigens and CD16, as well as novel trispecific nanobodies targeting PD-L1, 4-1BB, and NKG2A, have significantly inhibited tumor growth in preclinical models. Cytokine and metabolic regulation, from IL-15 superagonists to intermittent fasting-induced fatty acid oxidation, offers a third route to restoring NK cell fitness.

The advantages of NK cells over T cells are multidimensional. They recognize cells that have lost MHC class I expression, a common consequence of genomic instability in solid tumors, without needing HLA-restricted antigen presentation. Their low risk of graft-versus-host disease and lack of HLA-matching requirements make them candidates for true off-the-shelf products, in contrast to the individualized CAR-T manufacturing process that takes at least three weeks. NK cells can be derived from cord blood, peripheral blood, induced pluripotent stem cells, or immortalized NK-92 cell lines, enabling standardized scaled production. They also rely more on oxidative phosphorylation than glycolysis, giving them better energy efficiency and fatigue resistance in the hostile tumor microenvironment, and their endogenous interferon-gamma can reprogram tumor-associated macrophages from a tumor-promoting M2 phenotype to an antitumor M1 phenotype.

Safety data so far support this optimism. CAR-NK therapy has shown extremely low incidence of cytokine release syndrome and neurotoxicity, with no definitive reports of grade 3 or higher CRS or immune effector cell-associated neurotoxicity syndrome to date. But the review warns that cardiotoxicity is broadly relevant across immunotherapies, and the safety advantages of NK cells should not be mistaken for absence of risk. Immune checkpoint inhibitor-related cardiotoxicity occurs in roughly 1 to 2 percent of patients with a fatality rate of up to 46 percent, significantly higher than myocardial injury from conventional chemotherapy. In CAR-T treatment, cardiovascular adverse events occur in 20.5 percent of patients, with hypotension and tachycardia presenting as hyperacute events within a median of 6 to 21 days.

The mechanisms of immune-mediated cardiac injury offer a preview of what could go wrong with NK cells. Cytokine release directly damages myocardial mitochondria and disrupts calcium homeostasis through IL-6, TNF-alpha, and interferon-gamma, while activating endothelial cells and inducing microvascular obstruction. Alpha-myosin-specific T cells can drive myocarditis, although TCR sequencing suggests most expanded clones target unknown cardiac antigens, challenging the universality of molecular mimicry. A positive-feedback loop between CCR2-positive macrophages and CD8-positive T cells, mediated by the IL-12b/TNF/interferon-gamma axis, remodels the myocardial immune microenvironment, and NLRP3 inflammasome activation triggers gasdermin-E-dependent pyroptosis and release of mitochondrial DNA that activates the cGAS-STING pathway, causing irreversible tissue damage.

For NK cells specifically, several theoretical risks emerge. Although NK cells secrete less IL-6 and IL-1-beta than activated T cells, and their CRS profile is dominated by interferon-gamma, GM-CSF, and TNF-alpha with typically mild grade 1 to 2 manifestations, even mild CRS can trigger capillary leak syndrome, reducing effective circulating blood volume and myocardial perfusion. TNF-alpha downregulates SERCA2a and promotes ventricular remodeling. In mouse models of acute myocardial infarction, mature NK cells massively infiltrate ischemic myocardium through a CCR2-dependent pathway and their granzyme B directly induces cardiomyocyte apoptosis, while granzyme B can also enter vascular smooth muscle cells without perforin assistance. HER2, a common CAR-NK target antigen, has basal expression in normal cardiomyocytes, and although preclinical studies have not shown toxicity against nonmalignant HER2-positive cells, those conclusions rest on short-term in vitro co-culture that cannot simulate the long-term in vivo immune environment.

Engineered persistence introduces further uncertainty. IL-15 and IL-21 both signal through the JAK1/JAK3-STAT5 axis, which in pressure-overload heart failure models directly drives fibroblast activation and type I collagen deposition. Chronic low-grade IL-15 exposure from CAR-NK cells persisting in vivo for several weeks may induce subclinical interstitial remodeling, and IL-15 has been shown to enhance NK cell glycolysis, potentially creating energy competition with cardiomyocytes that depend on oxidative phosphorylation. Combination with PD-1 inhibitors may amplify interferon-gamma-driven cardiomyocyte iNOS expression and nitric oxide production, while prior anthracycline chemotherapy leaves mitochondria leaking reactive oxygen species that can create a second hit when immunotherapy triggers overlapping autoimmune and inflammatory responses.

The knowledge gaps are stark. No prospective, multicenter study dedicated to the cardiovascular safety of NK cell products has yet been conducted; all reports of arrhythmia, heart failure, or myocarditis are scattered across case reports and secondary endpoint analyses. The CTCAE v5.0 grading system classifies events by absolute values alone, overlooking temporal dynamics and recovery trajectories, so subclinical injuries go underreported. Median follow-up in most NK cell trials is less than two years, while delayed cardiomyopathy and immune-mediated vasculitis often manifest years to more than a decade after treatment. Biomarker cutoffs for troponin and NT-proBNP validated in CAR-T contexts have not been established for CAR-NK, and advanced imaging parameters such as cardiac magnetic resonance T1 values and global longitudinal strain have not been formally incorporated into any NK cell trial.

The review proposes a path forward anchored in cardio-oncology collaboration. Baseline risk stratification should integrate the HFA-ICOS score with solid-tumor-specific factors such as chronic hypoxia and malnutrition, and with clonal hematopoiesis of indeterminate potential, an emerging biomarker associated with IL-6-driven endothelial activation after immune stimulation. Dynamic monitoring should combine high-sensitivity troponin, NT-proBNP, electrocardiography, and cardiac magnetic resonance, with baseline ferritin and IL-6 levels included as validated predictors of CRS-related cardiac dysfunction. The microRNA miR-145, negatively correlated with IL-6 and TNF-alpha, deserves evaluation as a diagnostic and potentially cardioprotective marker. For confirmed immune-related myocarditis, pulse methylprednisolone followed by mycophenolate mofetil maintenance is recommended, while tocilizumab should be reserved for CRS-associated cardiac dysfunction to avoid excessive suppression of antitumor immunity.

Deeper cardiovascular monitoring also raises ethical tensions around economic burden, psychological anxiety, and privacy, requiring a balance between scientific rigor and patient wellbeing. Elevating cardiovascular safety to a core dimension of efficacy evaluation could drive developers to optimize NK cell product design at the source. If those gaps are filled, the authors conclude, NK cell-based immunotherapy could become a more efficient, safer, shorter-cycle, and lower-cost option in solid tumor therapy, but only once its cardiac risks move from inference to evidence.

Subject of Research: NK cell-based immunotherapy for solid tumors and its cardiovascular safety

Article Title: Progress in NK cell-based immunotherapy for solid tumors and an exploration of its cardiovascular safety

Article References: Chen, J., Shen, J., Fu, X., Jiang, M., Liu, R., Qiao, Q., & Hu, Y. (2026). Progress in NK cell-based immunotherapy for solid tumors and an exploration of its cardiovascular safety. Frontiers in Cell and Developmental Biology, 14, Article 1927923. https://doi.org/10.3389/fcell.2026.1927923

Image Credits: AI Generated

DOI: 10.3389/fcell.2026.1927923

Keywords: NK cells, CAR-NK, solid tumors, immunotherapy, cardiotoxicity, cytokine release syndrome, tumor microenvironment, immune checkpoint inhibitors, cardio-oncology, granzyme B, IL-15, myocarditis