Engineering CAR-NK Cells to Overcome Tumor Microenvironment (TME) Barriers in Solid Tumors

Ishika Sharma; Pramod Kumar; Monika Asthana

doi:10.55524/ijirem.2025.12.6.26

Abstract

In the recent years, cell-based immunotherapies have transformed the perspective of cancer treatment. Among these, the Chimeric Antigen Receptor- Natural Killer (CAR-NK) cells are gaining more attention due to their ability to recognize tumor cells without prior sensitization and a comparatively favourable safety profile. CAR-NK cells have shown promising results for haematological malignancies but appeared to slow down as interest passed to solid tumors. The Tumor micro- environment (TME) presents hostile conditions that weaken NK cells before they can act effectively. The TME confines NK cells' movement, exhausts energy reserves, and dampens cytotoxic signals, all of which could be attributed to reduced oxygen levels, competition for nutrients, suppressive cytokines, and the physical density of the tumor stroma. Several strategies address these issues, from improving NK-cell tumor-tracking with chemokine receptors, to supporting their activity with cytokine armoring, enhancing metabolic resilience in hypoxic regions, and engineering of their receptors to resist inhibitory signals. Newer ideas, such as conditional circuits like SynNotch, controlled cytokine release systems, CRISPR-edited NK cells, and iPSC-derived NK banks which can be used more broadly, may prove to be more effective. The field is clearly moving beyond early safety testing towards building durable responses in the face of a suppressive TME. Future success will likely depend not on one single design, but on combining several engineering strategies that allow these cells to adapt and survive within complex tumor settings.

Keywords

CAR-NK Cells, Solid Tumors, Tumor Microenvironment (TME), Cytokine Armoring, Chemokine Receptors.

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Cites this article as

I. Sharma, P. Kumar, M. Asthana, "Engineering CAR-NK Cells to Overcome Tumor Microenvironment (TME) Barriers in Solid Tumors", International Journal of Innovative Research in Engineering and Management (IJIREM), Vol-12, Issue-6, Page No-156-164, 2025. Available from: https://doi.org/10.55524/ijirem.2025.12.6.26