New insights into natural killer cell brakes point to more effective combination cancer therapies

A new comprehensive review reveals that harnessing natural killer (NK) cells by blocking their “off-switches” could significantly enhance cancer immunotherapy, providing new avenues for treating solid tumors and blood cancers that currently evade therapies.

Blocking Natural Killer Cell Brakes

Cancer cells often evade the immune system by exploiting molecular checkpoints on NK cells—key sentinels of our innate defenses. By detailing how these checkpoints function and surveying the latest preclinical and early clinical efforts to block them, this review lays the groundwork for more effective combination treatments.

“Understanding these ‘off-switches’ on NK cells has been like finding hidden fault lines in tumor defenses,” says Prof. Quan Cheng. “Our review not only maps these pathways in detail but also highlights actionable targets that could improve how we combine existing therapies.”

Success in this area could lead to better outcomes for patients, spur investment in novel biotech approaches (such as gene editing and engineered cell therapies), and inform healthcare policies that support next-generation immunotherapies.

Restoring Natural Killer Cell Power: From Preclinical Breakthroughs to Early Trials and Precision Engineering

The authors outline how NK cell checkpoints fall into two broad categories: surface receptors (such as NKG2A, KIRs, TIGIT, PD-1) and internal regulators (including BIM, Cbl-b, EZH2). They describe preclinical studies showing that blocking individual inhibitory receptors can restore NK cell killing in lab and animal models and that combining multiple checkpoint inhibitors or adding them to standard therapies often yields more substantial anti-tumor effects. Early clinical trials targeting NKG2A (e.g., monalizumab) and KIRs (e.g., lirilumab), particularly when combined with PD-1/PD-L1 inhibitors or tumor-targeting antibodies, have demonstrated acceptable safety profiles and initial signs of benefit in cancers such as head and neck, lung, and colorectal tumors. The review also highlights emerging precision approaches—using gene editing to remove inhibitory receptors or engineering CAR-NK cells with tailored targeting—that promise more specific recognition of cancer cells with potentially fewer side effects.

Decoding Natural Killer Signaling: Bridging Complex Lab Discoveries to Safe Clinical Testing

Behind the comprehensive review, the authors conducted a thorough survey of laboratory and animal research mapping the molecular pathways that regulate NK cell activation or inhibition. They reviewed data from a range of early-phase clinical trials testing antibodies against NK cell checkpoints, and they examined studies on advanced techniques such as CRISPR editing and CAR-NK engineering. Throughout, they translate complex signaling details into clear descriptions of how these checkpoints operate and how their blockade can be tested safely.

“Translating intricate signaling cascades into a roadmap for clinical design was challenging but essential,” explains Prof. Quan Cheng. “We aimed to make the mechanisms accessible so researchers and clinicians can rapidly iterate on promising strategies.”

A Roadmap to Next-Generation Natural Killer Therapies

By detailing the mechanisms through which tumors exploit NK cell checkpoints and summarizing strategies to block them, this review provides a practical roadmap for developing and refining NK-based immunotherapies. As these approaches advance toward broader clinical testing, they hold promise to expand the toolbox against cancers that evade existing treatments, offering hope for improved patient outcomes.

Published in Research in June 2025, the review was authored by researchers from the following institutions: Donghai County People's Hospital (Affiliated Kangda College of Nanjing Medical University), Shanghai Jiao Tong University School of Medicine, Naval Medical University (Second Military Medical University), Chinese Academy of Medical Sciences and Peking Union Medical College; Central South University, and Southern Medical University.

Sources: https://spj.science.org/doi/10.34133/research.0723