CAR-NK Cells: Harnessing the Power of Natural Killers for Advanced Cancer Therapy

Filipa D. dos Reis^1,2,3Yanis Saidani⁴Paula Martín-Rubio⁵Rebeca Sanz-Pamplona^5,6,7Ana Stojanovic^8,9Margareta P. Correia^1,10,2*

• ¹Cancer Biology & Epigenetics Group, Research Center of IPO Porto (CI-IPOP)/CI-IPOP@RISE (Health Research Network), Portuguese Oncology Institute of Porto (IPO-Porto), Porto, Portugal
• ²Porto Comprehensive Cancer Centre, Portuguese Oncology Institute, Porto, Portugal
• ³Doctoral Program in Biomedical Sciences, ICBAS - School of Medicine and Biomedical Sciences, University of Porto, Porto, Portugal
• ⁴Aix Marseille Univ, CNRS, INSERM, Institut Paoli-Calmettes, CRCM, Marseille, France
• ⁵Cancer Heterogeneity and Immunomics (CHI), University Hospital Lozano Blesa, Aragon Health Research Institute (IISA), Zaragoza, Aragon, Spain
• ⁶Aragonese Foundation for Research and Development (ARAID), Zaragoza, Spain
• ⁷CIBERESP, Instituto de Salud Carlos III, Madrid, Spain
• ⁸Department of Immunobiochemistry, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
• ⁹Mannheim Institute for Innate Immunoscience (MI3), Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
• ¹⁰Department of Pathology and Molecular Immunology, ICBAS - School of Medicine & Biomedical Sciences, University of Porto, Porto, Portugal

Generation of Chimeric Antigen Receptors (CARs) presented a significant advance in the field of immunotherapy, allowing the targeting of cell-surface expressed molecules in an MHC-independent manner. Arming NK cells with CARs merges their innate natural cytotoxicity with the refined precision of targeted antigen recognition. The success of these therapies hinges on selecting the right tumorspecific targets to ensure effective activation and avoid self-reactivity. Optimization of CAR design and targeting is based on NK cell intrinsic properties (CAR modules and sources of NK cells), as well as on NK-tumor cell interactions (multi-antigen, multi-step, multi-switch). Additionally, the dynamics of tumor infiltration and adaptation to the tumor microenvironment play a critical role in CAR-NK efficacy. Combining CAR-NK therapies with chemotherapy, radiotherapy, checkpoint inhibitors, and emerging approaches like epigenetic modulators and oncolytic viruses, may address some of these challenges. The development of CAR-NK strategies for metastatic disease is especially promising, though the complexities of metastasis require refined targeted designs. As immunomics and multiomics continue to evolve, the potential for designing more effective CAR-NK therapies expands. As results from preclinical and clinical trials unfold, a multidisciplinary approach integrating all those aspects will be key to unlock the full potential of CAR-NK cell-based adoptive transfers.