Open Access
REVIEW
Advances in Metabolic Reprogramming and Immune Regulatory Mechanisms in Lung Cancer
Xiaomeng Li1,2, Xuejiao Li2, Hongbo Wu1,*, Rui Li1,*
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 Author: 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 https://doi.org/10.32604/or.2026.076176
Received 15 November 2025; Accepted 03 February 2026; Published online 02 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.
Keywords
Lung cancer; metabolic reprogramming; immune evasion; tumor microenvironment; metabolic-immune axis
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