What makes natural killer cells so attractive as an anti-cancer weapon is their biology. Unlike cytotoxic T cells, which must be primed against a specific antigen before they can attack, NK cells are hardwired to detect and destroy transformed tissue on contact, without prior sensitization. They patrol the body constantly, integrating activating and inhibitory signals through a sophisticated array of germline-encoded receptors. When a cell loses the surface expression of major histocompatibility complex class I molecules, a common immune-evasion trick employed by tumors, the inhibitory brakes on NK cells are released and the killer cell delivers its lethal hit through the polarized release of lytic granules containing perforin and granzymes. NK cells also deploy activating receptors such as NKG2D and the natural cytotoxicity receptors NKp30, NKp44, and NKp46, which recognize stress-induced ligands upregulated on malignant cells. Beyond direct killing, they shape the broader immune response by secreting interferon-gamma and tumor necrosis factor alpha, which in turn promote the maturation of dendritic cells and support T cell priming, making them both executioners and orchestrators of antitumor immunity.

The liver, however, is a uniquely hostile arena for these cells. The review devotes considerable attention to the hepatocellular carcinoma tumor microenvironment, describing it as a formidable barrier that systematically disables NK cell function. Chronic exposure to transforming growth factor beta, an immunosuppressive cytokine abundantly produced in cirrhotic and tumor-bearing livers, downregulates activating receptors and blunts cytotoxicity. Persistent hypoxia, a hallmark of rapidly growing tumors with disorganized vasculature, further erodes NK cell metabolism and effector function. Perhaps most strikingly, the review highlights metabolic exhaustion driven by lipid accumulation: tumor cells and their supporting stroma flood the microenvironment with lactic acid and lipids, reprogramming NK cell metabolism and starving the cells of the glycolytic capacity they need to mount an effective attack. Studies cited in the review show that lactate dehydrogenase-associated lactic acid production directly blunts tumor immunosurveillance by both T and NK cells, and that fructose-1,6-bisphosphatase-induced inhibition of glycolysis cripples NK cell function during tumor progression.

The clinical evidence of NK cell dysfunction in liver cancer is equally sobering. Single-cell sequencing studies of human liver tumors have mapped the landscape of infiltrating immune cells and revealed that tumor-resident NK cells are phenotypically and functionally compromised. Tissue-resident CD56-bright NK cells enriched in the adult human liver, characterized by high Eomes and low T-bet expression, show reduced proinflammatory potential compared with their blood counterparts. In patients with hepatocellular carcinoma, myeloid-derived suppressor cells inhibit NK cell activity through the NKp30 receptor, and elevated levels of soluble NKG2D ligands and immunomodulatory molecules such as DKK3 further dampen antitumor responses. Exhaustion markers tell a similar story: NK cells expressing the inhibitory receptors TIGIT, TIM-3, CD96, and programmed death 1 correlate with disease progression in hepatitis B virus-related hepatocellular carcinoma, and high CD96 expression on NK cells predicts poorer prognosis. Downregulation of the PR/SET domain 10 protein has also been implicated as an underlying mechanism of NK cell dysfunction in these patients.

Against this backdrop, the review maps out the therapeutic strategies now being pursued to restore or supercharge NK cell activity. The most straightforward approach is cytokine-supported adoptive transfer: NK cells harvested from patients or healthy donors are expanded ex vivo using cytokines such as interleukin-15 and interleukin-21, then infused back in large numbers. Interleukin-15 has shown particular promise, with experimental work demonstrating that it can overcome hepatocellular carcinoma-induced NK cell dysfunction. The foundational proof of concept came from early clinical studies showing successful adoptive transfer and in vivo expansion of haploidentical NK cells in patients with cancer, and more recent trials have extended the approach to liver cancer specifically. A phase I trial of NK cell infusion in patients with recurrent hepatocellular carcinoma after liver transplantation reported that the treatment was well tolerated and showed preliminary efficacy, while an open-label phase I study protocol is testing adoptive immunotherapy with NK cells derived from peripheral blood CD34-positive stem cells to prevent recurrence after curative hepatectomy.

Genetic engineering has pushed the field considerably further. Chimeric antigen receptor-engineered NK cells, or CAR-NK cells, are equipped with synthetic receptors that redirect their killing capacity toward tumor-associated antigens. In hepatocellular carcinoma, the leading targets are glypican-3, or GPC3, a cell surface proteoglycan abundantly expressed on malignant hepatocytes, and CD147, a transmembrane glycoprotein implicated in tumor invasion. GPC3-specific CAR-NK cells have been developed and validated in preclinical models, and anti-CD147 chimeric antigen receptors have demonstrated efficacy against hepatocellular carcinoma cells. A first-in-human phase 1 trial of induced pluripotent stem cell-derived CD19-directed CAR-NK cells in B-cell lymphoma has provided an important clinical template for the broader platform, demonstrating that off-the-shelf, genetically defined NK cell products can be manufactured and safely administered. The review notes, however, that head-to-head comparisons suggest CAR-T cells can outperform CAR-NK cells in some CAR-mediated effector functions, underscoring that the technology still has room to mature.

A parallel and rapidly evolving strategy involves bispecific and trispecific killer cell engagers, known as BiKEs and TriKEs. These antibody-like molecules physically bridge NK cells to tumor cells while simultaneously delivering activating signals. Trispecific killer engagers incorporating an interleukin-15 linker have been shown to direct NK cells toward CD33-positive targets while inducing persistence, in vivo expansion, and enhanced function. Tri-specific engagers targeting mesothelin have been used to steer NK cells toward lung cancer, and the platform is now being applied to liver cancer: a GPC3-targeted NK engager bispecific antibody has entered a phase 1/2a clinical trial in patients with hepatocellular carcinoma, and novel NKp46-based engagers targeting GPC3 have undergone preclinical characterization. Recent work has also produced therapeutic bispecific antibodies targeting CD16A on NK cells and GPC3 on tumor cells, and tetravalent bispecific engagers designed to activate NK cells against cancer without mediating fratricide, a key safety consideration when the targeting antigen is also expressed on the therapeutic cells themselves.

Combination strategies form another pillar of the review. The multikinase inhibitor sorafenib, a longstanding standard of care in advanced hepatocellular carcinoma, has been shown to perpetuate cellular anticancer effector functions by modulating crosstalk between macrophages and NK cells, and preclinical studies of sorafenib combined with memory-like NK cells have reported encouraging antitumor activity in models of the disease. Xenograft experiments mapping the signaling pathways engaged by combined sorafenib and NK cell therapy have reinforced the mechanistic rationale. Lenvatinib, a newer tyrosine kinase inhibitor, appears to activate antitumor immunity by suppressing immunoinhibitory infiltrates in the tumor microenvironment, creating a permissive setting for adoptive cell therapy. Immune checkpoint blockade is also being explored in combination with NK cell approaches, with single-cell RNA sequencing in humanized mice revealing antitumor potency of NK and CD8-positive T cells when PD-1 and TIGIT are co-targeted. Even oncolytic viruses have entered the picture, with an engineered measles virus shown to enhance the antitumor responses of adoptively transferred NKG2D-positive immune cells in hepatocellular carcinoma models.

The review is candid about the knowledge gaps that still separate laboratory promise from routine clinical benefit. The complex interplay between NK cells and the tumor microenvironment remains incompletely understood, particularly the roles of hepatic stellate cells and cancer-associated fibroblasts, which secrete chemokines such as CXCL5 that promote immunosuppressive signaling. The metabolic reprogramming of NK cells in the lipid-rich liver environment, the mechanosensory properties that govern NK cell function in dense tumor tissue, and the education and licensing processes that calibrate NK cell responsiveness all demand further study. Chronic alcohol consumption, a major risk factor for liver disease, has been shown to impair peripheral NK cell development by reducing interleukin-15 availability, adding another layer of complexity in a patient population where such exposures are common. The authors argue that resolving these questions is essential for optimizing NK cell immunotherapy and improving prognostic outcomes.

Nevertheless, the trajectory of the field is unmistakably upward. From the NK-92 cell line, whose three decades of use have shaped much of modern NK cell research, to iPSC-derived CAR-NK products and GPC3-directed engagers now in clinical trials, the toolkit for deploying natural killer cells against hepatocellular carcinoma has expanded dramatically in a short period. The review’s synthesis suggests that the coming years will be defined by rational combinations, pairing engineered NK cells with kinase inhibitors, checkpoint blockade, and metabolic interventions designed to neutralize the tumor microenvironment’s defenses. For a cancer that has long resisted immunotherapeutic advances and continues to claim hundreds of thousands of lives each year, the renaissance in NK cell biology may represent the most credible path yet toward durable, off-the-shelf immunotherapy for liver cancer, and the scientific foundation laid by this comprehensive analysis offers researchers a clear map of both the opportunities and the obstacles that lie ahead.

Subject of Research: Natural killer cell-based immunotherapy for hepatocellular carcinoma

Article Title: Natural killer cell-based therapy for hepatocellular carcinoma (HCC): A literature review

Article References: Widowati, W., Wargasetia, T. L., Sadri, B., Nainggolan, I. M., Azis, R., Rifana, S. D., Rismani, E., & Vosough, M. (2026). Natural killer cell-based therapy for hepatocellular carcinoma (HCC): A literature review. Medical Oncology, 43(11), Article 293. https://doi.org/10.1007/s12032-026-03393-5

Image Credits: AI Generated

DOI: 10.1007/s12032-026-03393-5

Keywords: natural killer cells, hepatocellular carcinoma, immunotherapy, CAR-NK cells, tumor microenvironment, glypican-3, bispecific killer cell engagers, interleukin-15, liver cancer, adoptive cell therapy, NK cell dysfunction, sorafenib