Tumor-intrinsic metabolic reprogramming and how it drives resistance to anti-PD-1/PD-L1 treatment

The development of immune checkpoint blockade (ICB) therapies has been instrumental in advancing the field of immunotherapy. Despite the prominence of these treatments, many patients exhibit primary or acquired resistance, rendering them ineffective. For example, anti-programmed cell death protein 1 (anti-PD-1)/anti-programmed cell death ligand 1 (anti-PD-L1) treatments are widely utilized across a range of cancer indications, but the response rate is only 10%-30%. As such, it is necessary for researchers to identify targets and develop drugs that can be used in combination with existing ICB therapies to overcome resistance. The intersection of cancer, metabolism, and the immune system has gained considerable traction in recent years as a way to comprehensively study the mechanisms that drive oncogenesis, immune evasion, and immunotherapy resistance. As a result, new research is continuously emerging in support of targeting metabolic pathways as an adjuvant to ICB to boost patient response and overcome resistance. Due to the plethora of studies in recent years highlighting this notion, this review will integrate the relevant articles that demonstrate how tumor-derived alterations in energy, amino acid, and lipid metabolism dysregulate anti-tumor immune responses and drive resistance to anti-PD-1/PD-L1 therapy.