Research Progress on Lactate-Mediated Tumor Metabolic Microenvironment-Driven Immunotherapy and Metabolic Reprogramming Strategies
DOI:
https://doi.org/10.61173/xtckva87Keywords:
-Tumor metabolic microenvironment, im-munotherapy resistance, lactate metabolism, metabolic reprogramming, clinical translationAbstract
Abnormal metabolites (such as lactate) in the tumor metabolic microenvironment (TME) significantly affect the efficacy of immunotherapy by reshaping the function of immune cells. However, the mechanism of lactate-mediated immunosuppression has not been fully elucidated, and the clinical translation of targeted metabolic intervention strategies faces challenges of drug resistance and toxicity. This study systematically reviewed the bidirectional regulatory mechanism of lactate on CD8+ T cells and regulatory T cells (Treg), integrated the TCGA/GEO database to analyze the association between metabolic enzyme gene expression and prognosis, and compared the preclinical and clinical trial data of targeted lactate metabolism. The results showed that: (1) lactate inhibited T cell glycolytic activity by acidifying the microenvironment, while activating the HIF-1α/GPR81 signaling axis to promote Treg differentiation; (2) LDHA inhibitors (such as GSK2837808A) and MCT1/4 blockers can reduce TME lactate levels and enhance the efficacy of PD-1 antibodies; (3) Clinical translation needs to address the problems of metabolic targeted drug delivery efficiency and the lack of patient stratification markers. In summary, targeting lactate metabolism is a key breakthrough in reversing resistance to immunotherapy, and its efficacy depends on precise intervention guided by multi-omics. This article suggests that dynamic lactate monitoring technology and nano-drug delivery systems should be developed in the future, and metabolic-immune dual-target combined treatment plans should be designed to optimize clinical outcomes.
References
[1] K. G. De La Cruz-López et al., “Lactate in the regulation of tumor microenvironment and therapeutic approaches,” Front. Oncol., vol. 9, p. 1143, 2019.
[2] M. Jiang et al., “From metabolic byproduct to immune modulator: the role of lactate in tumor immune escape,” Front. Immunol., vol. 15, p. 1492050, 2024.
[3] L. Sun et al., “T cells in health and disease,” Signal Transduct. Target Ther., vol. 8, no. 1, p. 235, 2023.
[4] S. Liu et al., “USP1 promotes the aerobic glycolysis and progression of T-cell acute lymphoblastic leukemia via PLK1/ LDHA axis,” Blood Adv., vol. 7, no. 13, pp. 3099–3112, 2023.
[5] W. Ren et al., “mTORC1 signaling and IL-17 expression: defining pathways and possible therapeutic targets,” Eur. J. Immunol., vol. 46, no. 2, pp. 291–299, 2016.
[6] L. Yang et al., “Adenosine signaling in tumor-associated macrophages and targeting adenosine signaling for cancer therapy,” Cancer Biol. Med., vol. 21, no. 11, pp. 995–1011, 2024.
[7] Z. Gurel et al., “Metabolic modulation of melanoma enhances the therapeutic potential of immune checkpoint inhibitors,” Front. Oncol., vol. 14, p. 1428802, 2024.
[8] H. Yokota et al., “Lactate, choline, and creatine levels measured by vitro 1H-MRS as prognostic parameters in patients with non-small-cell lung cancer,” J. Magn. Reson. Imaging, vol. 25, no. 5, pp. 992–999, 2007.
[9] G. Pathria et al., “Targeting the Warburg effect via LDHA inhibition engages ATF4 signaling for cancer cell survival,” EMBO J., vol. 37, no. 20, 2018.
[10] S. C. Tripathi et al., “Targeting metabolic vulnerabilities of cancer: small molecule inhibitors in clinic,” Cancer Rep., vol. 2, no. 1, p. e1131, 2019.
[11] A. Sarma et al., “Ligand nanoparticle conjugation approach for targeted cancer chemotherapy,” in Nano Medicine and Nano Safety: Recent Trends and Clinical Evidences, M. K. Das and Y. V. Pathak, Eds. Singapore: Springer, 2020, pp. 377–403.
[12] T. Liu et al., “Role of human monocarboxylate transporter 1 (hMCT1) and 4 (hMCT4) in tumor cells and the tumor microenvironment,” Cancer Manag. Res., vol. 15, pp. 957–975, 2023.
[13] N. J. Curtis et al., “Pre-clinical pharmacology of AZD3965, a selective inhibitor of MCT1: DLBCL, NHL and Burkitt’s lymphoma anti-tumor activity,” Oncotarget, vol. 8, no. 41, pp. 69219–69236, 2017.
[14] H. Ando et al., “Increasing tumor extracellular pH by an oral alkalinizing agent improves antitumor responses of anti- PD-1 antibody: implication of relationships between serum bicarbonate concentrations, urinary pH, and therapeutic outcomes,” Biol. Pharm. Bull., vol. 44, no. 6, pp. 844–852, 2021.
[15] S. Jiang et al., “Lactate-oxidase-instructed cancer diagnosis and therapy,” Adv. Mater., vol. 35, no. 19, p. 2207951, 2023.
[16] F. Xi et al., “Microbubbles ultrasonic cavitation regulates tumor interstitial fluid pressure and enhances sonodynamic therapy,” Front. Oncol., vol. 12, p. 852454, 2022.
[17] B. Cerbelli et al., “CD73 expression and pathologic response to neoadjuvant chemotherapy in triple negative breast cancer,” Virchows Arch., vol. 476, no. 4, pp. 569–576, 2020.
[18] M. Saigí et al., “Unraveling the intricacies of CD73/ adenosine signaling: the pulmonary immune and stromal microenvironment in lung cancer,” Cancers, vol. 15, no. 23, 2023.
[19] L. B. S. Aulin et al., “Biomarker-guided individualization of antibiotic therapy,” Clin. Pharmacol. Ther., vol. 110, no. 2, pp. 346–360, 2021.
Downloads
Published
Issue
Section
License
Copyright (c) 2025 by the authors.
This work is licensed under a Creative Commons Attribution 4.0 International License.
