The tumor microenvironment drives NK cell metabolic dysfunction leading to impaired antitumor activity

Abstract

NK cells represent key players capable of driving antitumor immune responses. However, the potent immunosuppressive activity of the tumor microenvironment (TME) may impair their effector function. Here, we strengthen the importance of metabolic interactions between NK cells and TME and propose metabolic dysfunction as one of the major mechanisms behind NK failure in cancer treatment. In particular, we described that TME has a direct negative impact on NK cell function by disrupting their mitochondrial integrity and function in pediatric and adult patients with primary and metastatic cancer. Our results will help to design new strategies aimed at increasing the NK cell antitumor efficacy by their metabolic reprogramming. In this regard, we reveal an unprecedented role of IL15 in the metabolic reprogramming of NK cells enhancing their antitumor functions. IL15 prevents the inhibitory effect of soluble factors present in TME and restores both the metabolic characteristics and the effector function of NK cells inhibited by exposure to malignant pleural fluid. Thus, we propose here that IL15 may be exploited as a new strategy to metabolically reprogram NK cells with the aim of increasing the efficacy of NK-based immunotherapy in a wide range of currently refractory adult and pediatric solid tumors.

Metabolic adaptations determine whether natural killer cells fail or thrive within the tumor microenvironment

“…These metabolic dysfunctions were also induced in healthy donor pbNK cells when exposed to the TME 7 . Similarly, pbNK cells incubated with the malignant pleural effusion of patients with lung cancer have lower mitochondrial mass and function, and impaired OxPhos 17 . These mitochondrial defects were correlated with a reduced cytotoxic capacity of pbNK cells 17 .…”

“…7 Similarly, pbNK cells incubated with the malignant pleural effusion of patients with lung cancer have lower mitochondrial mass and function, and impaired OxPhos. 17 These mitochondrial defects were correlated with a reduced cytotoxic capacity of pbNK cells. 17 Overall, NK cell metabolism in a crucial factor in determining NK cell antitumor functions in the TME.…”

“…17 These mitochondrial defects were correlated with a reduced cytotoxic capacity of pbNK cells. 17 Overall, NK cell metabolism in a crucial factor in determining NK cell antitumor functions in the TME.…”

Tumor Metabolism-Rewriting Nanomedicines for Cancer Immunotherapy

“…NK cells can exert tumoricidal function by releasing cytolytic granules and cytotoxic cytokines, which are controlled by a complex array of activating and inhibitory receptors. However, the metabolic impairment promotes the dysfunction of NK cells within TME. , To enhance the NK cell-mediated innate antitumor immunity by reprogramming its cellular metabolism, a immunosensitizer (BPQDs@HSA) was constructed by encapsulating black phosphorus (BP) quantum dots (QDs) in human serum albumin (HSA) (Figure A, Table ). In this study, the author found that the BPQDs@HSA treatment enhanced the expression of TLR-5, TLR-9, and NF-κB in NK cells (Figure B).…”

DNAM-1 chimeric receptor-engineered NK cells: a new frontier for CAR-NK cell-based immunotherapy

“…In contrast, it is noteworthy that NK cells in cancer patients show impaired functions accompanied by a poor ability to infiltrate the tumor microenvironment (TME), as tumor cells adopt different various immune evasion mechanisms (10)(11)(12)(13)(14)(15)(16)(17). Therefore, the adoptive transfer of ex vivo expanded and activated allogeneic NK cells for immunotherapy turns out to be a strategic clinical adoption to help cancer patients to fight tumor cells, thus attracting increasing interest in the past decade (18).…”