Cancer is fundamentally a disease of dysregulated metabolism in which malignant cells reprogram standard biochemical pathways. This reprogramming or rewiring can lead to unrestrained proliferation, evasion of immune surveillance and resistance to therapy. Non-small cell lung cancer (NSCLC) is particularly relevant to this concept, as distinct molecular subsets exhibit unique metabolic phenotypes that influence tumor behavior and treatment response (Han et al., 2023, Park et al., 2022). Among these subsets, anaplastic lymphoma kinase (ALK)-positive NSCLC represents a critical subset characterized by the oncogenic EML4-ALK fusion gene, an alteration that drives tumorigenesis through constitutive kinase activation (Herrera-Juarez et al., 2023, EML4-ALK, 2023, Nensi and Ashton, 2021). Analogous to the BCR-ABL fusion in chronic myeloid leukemia (CML), ALK rearrangements occur in approximately 4–6 % of NSCLC cases (Ou and Shirai, 2016). Affected patients have unique clinical characteristics, with a median age at diagnosis of only 52 years and a relatively large proportion of patients who have never smoked in their lives (Shaw et al., 2013, Chapman et al., 2016). The advent of ALK-targeted tyrosine kinase inhibitors (TKIs) has revolutionized the management of ALK-positive NSCLC, significantly improving progression-free survival and overall response rates (Lovly, 2024, Qi et al., 2024). Despite these advances, therapeutic resistance remains an inevitable challenge, leading to recurrence and limiting further clinical options. While resistance mechanisms have been extensively characterized at the genomic and molecular level, the metabolic adaptations that accompany ALK inhibitor resistance remain largely unexplored. Emerging evidence suggests that ALK-positive lung cancer is predominantly glycolytic, but also exhibits metabolic plasticity in response to targeted inhibition (Ma et al., 2016). Notably, tumor cells surviving ALK blockade undergo a metabolic shift from glycolysis to oxidative phosphorylation, a transition that enables persistence under therapeutic pressure (Rosell et al., 2023). This shift reflects a broader principle in oncology, that resistance mechanisms frequently exploit metabolic flexibility to sustain energy production and biosynthesis in the face of pharmacologic stress.

A growing body of research has shown the relationship between oncogenic signaling and metabolism in ALK-positive NSCLC (Elshatlawy et al., 2023, Nagano et al., 2019). The EML4-ALK fusion drives hyperactivation of multiple oncogenic pathways (Fig. 1). These pathways include PI3K-AKT-mTOR, JAK-STAT3 and RAS-MAPK, which in turn fuel metabolic reprogramming to meet the heightened anabolic and energetic demands of cancer cells (Moore et al., 2014). ALK-positive NSCLC has been shown to rely heavily on glycolysis, with increased uptake of glucose, fatty acids and amino acids to sustain proliferation. Despite this knowledge, comprehensive knowledge about metabolic alterations driving ALK-positive NSCLC remains limited and metabolic-based targeting has been largely unheeded. This gap in understanding represents an opportunity for therapeutic intervention.

A promising yet underexplored approach to overcoming resistance and enhancing treatment efficacy in ALK-positive NSCLC lies in targeting tumor metabolism through dietary interventions such as caloric restriction (CR). CR has demonstrated the ability to alter the energy and nutritional status of both tumor and immune cells, leading to metabolic stress that selectively impacts malignant cells while enhancing anti-tumor immune responses (Alidadi et al., 2021, Kopeina et al., 2017). Preclinical studies suggest that CR can modulate the metabolic profile of tumor-associated macrophages, shifting them from an immunosuppressive (M2-like) phenotype toward a pro-inflammatory (M1-like) phenotype to improve immune surveillance (Wang et al., 2023a). Additionally, CR has been shown to enhance T cell function and synergize with chemotherapy and targeted therapies in other malignancies (Asami et al., 2022). Given the parallels between ALK-positive NSCLC and other immune-cold tumors such as ovarian cancer, CR may offer a novel strategy to reprogram tumor and immune cell metabolism.

In this review, we explore the metabolic landscape of ALK-positive NSCLC, with a focus on how metabolic reprogramming contributes to tumor progression, therapeutic resistance and potential vulnerabilities that can be exploited for treatment. We begin with a broad overview of cancer metabolism, followed by an in-depth analysis of metabolic adaptations in ALK-positive lung cancer. We then discuss the implications of targeting these metabolic pathways through strategies such as caloric restriction and autophagy modulation. Finally, we examine future directions in integrating metabolic targeting with existing ALK-directed therapies, offering new avenues to enhance treatment efficacy and prevent disease recurrence. By bridging the gap between oncogenic signaling and tumor metabolism, this review aims to provide a foundation for novel, metabolism-driven therapeutic approaches in ALK-positive NSCLC.