Open Access

REVIEW

Advances in Metabolic Reprogramming and Immune Regulatory Mechanisms in Lung Cancer

Xiaomeng Li^1,2, Xuejiao Li², Hongbo Wu^1,*, Rui Li^1,*

1 Department of Respiratory Intervention, The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, No. 127, Dongming Road, Jinshui District, Zhengzhou, China
2 Department of Basic Medicine Science, North Henan Medical University, Xinxiang, China

* Corresponding Authors: Hongbo Wu. Email: ; Rui Li. Email:

(This article belongs to the Special Issue: Direct and Paracrine Interactions within the Tumor or Tumor and its  Microenvironment)

Oncology Research 2026, 34(4), 11 https://doi.org/10.32604/or.2026.076176

Received 15 November 2025; Accepted 03 February 2026; Issue published 23 March 2026

Abstract

Lung cancer remains the leading cause of cancer-related mortality worldwide, primarily driven by metabolic reprogramming and immune evasion mechanisms within tumor cells. To adapt to the nutrient-deprived tumor microenvironment (TME), lung cancer cells undergo profound metabolic reprogramming, characterized by enhanced glycolysis (the Warburg effect), increased glutamine dependency (mediated by GLS1), and accelerated lipid synthesis (involving enzymes such as FASN). These metabolic alterations not only remodel the TME but also dampen antitumor immune responses by promoting immunosuppressive cell populations (e.g., Tregs and M2 macrophages) and inhibiting effector functions of CD8⁺ T cells and natural killer (NK) cells. Critically, a bidirectional crosstalk operates between tumor cell metabolism and the immunosuppressive TME: metabolic reprogramming drives immune suppression through metabolite accumulation, whereas the immunosuppressive TME, in turn, promotes tumor cell adaptability—thus forming a positive feedback loop that reinforces immune evasion and therapy resistance. This review elucidates key molecular pathways governing metabolic reprogramming in lung cancer—spanning glucose, amino acid, and lipid metabolism—and their dynamic crosstalk with immune regulation, including epigenetic modifications and non-coding RNA-mediated mechanisms. Additionally, it evaluates emerging therapeutic strategies targeting the metabolic-immune axis, such as inhibitors of HK2 or GLS1 combined with anti-PD-1/PD-L1 agents, which aim to reverse immunosuppression and improve clinical outcomes. By synthesizing recent advances, this work provides a theoretical framework for precision oncology interventions, highlighting the potential of metabolic immunotherapies and future directions integrating AI and multi-omics data to overcome resistance in lung cancer.

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