Mitochondrial reprogramming in lung cancer: a therapeutic vulnerability and a strategy for reversing drug resistance

Abstract The conceptualization of mitochondria, previously restricted to their function as cellular ‘powerhouses’, has evolved to recognize their function as central coordinating hubs for the orchestration of cancer cell metabolism, signaling, and fate determination. Within the context of lung cancer, encompassing both non‐small cell lung cancer and small cell lung cancer, these organelles undergo profound functional and structural dysregulation integral to tumor initiation, progression, and most critically, therapeutic resistance. This review presents a synthesis of the burgeoning field of mitochondrial inhibitors as a strategic approach for lung cancer treatment, achieved by synthesizing detailed mechanistic and preclinical data into an evidence‐graded framework. This document first provides a delineation of the fundamental dysregulation of mitochondrial functions in lung cancer, inclusive of metabolic reprogramming toward oxidative phosphorylation dependency, particularly in distinct genetic contexts (e.g., LKB1 , SWI/SNF ‐mutant). Subsequent sections systematically categorize and analyze the major classes of mitochondrial inhibitors predicated upon their mechanisms of action, including electron transport chain inhibitors, pro‐apoptotic agents (e.g., B‐cell lymphoma 2/B‐cell lymphoma xL inhibitors), and modulators of metabolism and dynamics. A critical focus is applied to the role of these agents in the supersession of acquired resistance to established therapies, such as epidermal growth factor receptor‐tyrosine kinase inhibitors, chemotherapy, and immunotherapy. The translational landscape is consolidated herein by summarizing key clinical trials (including terminations precipitated by toxicity) and distinguishing small cell lung cancer specific vulnerabilities. Finally, the significant challenges of on‐target, off‐tumor toxicity and the crucial necessity for predictive biomarkers are addressed. Through the synthesis of these disparate fields into a unified, clinically oriented framework, it is posited that targeting mitochondrial vulnerabilities possesses the potential to overcome longstanding therapeutic hurdles in lung cancer. © 2026 The Pathological Society of Great Britain and Ireland.