Fuel for thought: targeting metabolism in lung cancer

For over a century, we have appreciated that the biochemical processes through which micro- and macronutrients are anabolized and catabolized-collectively referred to as "cellular metabolism"-are reprogrammed in malignancies. Cancer cells in lung tumors rewire pathways of nutrient acquisition and metabolism to meet the bioenergetic demands for unchecked proliferation. Advances in precision medicine have ushered in routine genotyping of patient lung tumors, enabling a deeper understanding of the contribution of altered metabolism to tumor biology and patient outcomes. This paradigm shift in thoracic oncology has spawned a new enthusiasm for dissecting oncogenotype-specific metabolic phenotypes and creates opportunity for selective targeting of essential tumor metabolic pathways. In this review, we discuss metabolic states across histologic and molecular subtypes of lung cancers and the additional changes in tumor metabolic pathways that occur during acquired therapeutic resistance. We summarize the clinical investigation of metabolism-specific therapies, addressing successes and limitations to guide the evaluation of these novel strategies in the clinic. Beyond changes in tumor metabolism, we also highlight how non-cellular autonomous processes merit particular consideration when manipulating metabolic processes systemically, such as efforts to disentangle how lung tumor cells influence immunometabolism. As the future of metabolic therapeutics hinges on use of models that faithfully recapitulate metabolic rewiring in lung cancer, we also discuss best practices for harmonizing workflows to capture patient specimens for translational metabolic analyses.