REVIEW article
Front. Immunol.
Sec. Cancer Immunity and Immunotherapy
THE METABOLIC ENVIRONMENT WITHIN SOLID TUMORS DRIVES A COMPLEX CROSSTALK BETWEEN MACROPHAGE AND NK CELLS
Karolinska Institutet, Stockholm, Sweden
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Abstract
Tumor cells use various immunosuppressive mechanisms to escape immune-mediated killing, which allows them to persist and thrive throughout the anti-tumor immune response. This "immune escape" phenomenon occurs when tumor cells display strategies to suppress the immune system (Caner, 2023). Cancer cells can evade immune monitoring by hindering antigen presentation, using negative regulation, and recruiting immunosuppressive cell populations, even when nonspecific immunity is naturally successful (Czajka-Francuz et al., 2023). As a result, immune cell effector activities are weakened, and anti-tumor immune responses are ineffective (Spada and Mukherjee, 2024). With the idea of strengthening immune cells' anticancer properties to stop cancer cells from escaping the immune system, immunotherapy was developed in response to this difficulty (Mbeunkui and Johann, 2009). Immunotherapies against hematological malignancies have demonstrated higher success than solid tumors (Huang et al., 2024). However, according to US 2020 data, solid tumor cases are ten times higher than hematological cancers (Siegel, Miller, and Jemal, 2020). From this perspective, solid tumor immunotherapy studies are of great importance. There is an obvious need for successful immunotherapies in solid tumors compared to hematological malignancies (Hays, 2022). Within this context, natural killer (NK) cells and macrophages are one of the key players in the anti-tumor immune response and play a central role in shaping immune activity within the tumor microenvironment. In this review, we propose that metabolic competition represents a central upstream driver between macrophages and NK cells in solid tumors, utilizing cytokine signaling, spatial organization, and nutrient status within the tumor microenvironment (TME).
Summary
Keywords
anti-tumor immunity, crosstalk, macrophage, Metabolic competition, Natural killer cells (NK cells), Solid tumor, tumor associate macrophages (TAM)
Received
16 October 2025
Accepted
17 February 2026
Copyright
© 2026 Cakirsoy Akyoney and Alici. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Evren Alici
Disclaimer
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