bims-mecami 2023-08-06 papers

Issue of 2023–08–06
two papers selected by
Oltea Sampetrean, Keio University

DNA Cell Biol. 2023 Aug 03.

Lipid Metabolic Regulatory Crosstalk Between Cancer Cells and Tumor-Associated Macrophages.

Shu Liu, Ying Ying Shen, Li Yang Yin, Jianghua Liu, Xuyu Zu.

In the tumor microenvironment, tumor-associated macrophages (TAMs) are one of the most abundant cell populations, playing key roles in tumorigenesis, chemoresistance, immune evasion, and metastasis. There is an important interaction between TAMs and cancer cells: on the one hand, tumors control the function of infiltrating macrophages, contributing to reprogramming of TAMs, and on the other hand, TAMs affect the growth of cancer cells. This review focuses on lipid metabolism changes in the complex relationship between cancer cells and TAMs. We discuss how lipid metabolism in cancer cells affects macrophage phenotypic and metabolic changes and, subsequently, how altered lipid metabolism of TAMs influences tumor progression. Identifying the metabolic changes that influence the complex interaction between tumor cells and TAMs is also an important step in exploring new therapeutic approaches that target metabolic reprogramming of immune cells to enhance their tumoricidal potential and bypass therapy resistance. Our work may provide new targets for antitumor therapies.

Keywords: cancer cells; lipid metabolism; targeting therapy; tumor-associated macrophages

DOI: https://doi.org/10.1089/dna.2023.0071

Nat Commun. 2023 Aug 04. 14(1): 4677

Targeting of SLC25A22 boosts the immunotherapeutic response in KRAS-mutant colorectal cancer.

Qiming Zhou, Yao Peng, Fenfen Ji, Huarong Chen, Wei Kang, Lam-Shing Chan, Hongyan Gou, Yufeng Lin, Pingmei Huang, Danyu Chen, Qinyao Wei, Hao Su, Cong Liang, Xiang Zhang, Jun Yu, Chi Chun Wong.

KRAS is an important tumor intrinsic factor driving immune suppression in colorectal cancer (CRC). In this study, we demonstrate that SLC25A22 underlies mutant KRAS-induced immune suppression in CRC. In immunocompetent male mice and humanized male mice models, SLC25A22 knockout inhibits KRAS-mutant CRC tumor growth with reduced myeloid derived suppressor cells (MDSC) but increased CD8+ T-cells, implying the reversion of mutant KRAS-driven immunosuppression. Mechanistically, we find that SLC25A22 plays a central role in promoting asparagine, which binds and activates SRC phosphorylation. Asparagine-mediated SRC promotes ERK/ETS2 signaling, which drives CXCL1 transcription. Secreted CXCL1 functions as a chemoattractant for MDSC via CXCR2, leading to an immunosuppressive microenvironment. Targeting SLC25A22 or asparagine impairs KRAS-induced MDSC infiltration in CRC. Finally, we demonstrate that the targeting of SLC25A22 in combination with anti-PD1 therapy synergizes to inhibit MDSC and activate CD8+ T cells to suppress KRAS-mutant CRC growth in vivo. We thus identify a metabolic pathway that drives immunosuppression in KRAS-mutant CRC.

DOI: https://doi.org/10.1038/s41467-023-39571-6