Targeting the powerhouse: A critical review of mitochondrial inhibitors as a therapeutic strategy in lung cancer

Lung cancer therapy is constrained by profound intrinsic and acquired resistance to targeted therapies and immunotherapy. To overcome this, a new therapeutic paradigm is emerging that targets the unique metabolic and survival dependencies of cancer cells. Mitochondria, the central hubs of metabolism, cell death, and signaling, represent a critical vulnerability. This review provides a new conceptual framework for understanding and targeting mitochondrial pathways in lung cancer. First, this review outlines the key “mitochondrial hallmarks” of lung cancer that create therapeutic windows, emphasizing the critical role of metabolic heterogeneity. Second, it provides a novel, mechanism-based classification of mitochondrial inhibitors into four major classes: (1) electron transport chain (ETC) inhibitors, (2) metabolic enzyme modulators, (3) apoptosis pathway modulators, and (4) mitochondrial quality control (MQC) disruptors. Third, this review critically analyzes the molecular mechanisms by which these inhibitors activate regulated cell death pathways (apoptosis, ferroptosis) and, most importantly, their potential in overcoming therapeutic resistance to standard-of-care. Fourth, it explores the mechanisms of mitochondrial crosstalk within the tumor microenvironment (TME), including intercellular transfer via tunneling nanotubes. Finally, this review presents a systematic review of the clinical landscape, synthesizing data from preclinical models and ongoing clinical trials. This review concludes by highlighting key limitations and future perspectives, positioning MQC and the mitochondrial unfolded protein response (UPRmt) as next-generation targets to improve patient outcomes.