Metabolic Barriers to Cancer Immunotherapy: Multiscale Mechanisms from Organelle Dysfunction to Organ-Specific Constraints.

Immune checkpoint blockade (ICB) has reshaped cancer therapy, yet primary resistance and acquired relapse remain common despite therapeutic targeting of inhibitory receptor pathways. This limitation suggests that checkpoint release may remain insufficient when antitumor lymphocytes lack the metabolic, organelle-level, spatial, or systemic conditions required for tissue entry, functional recovery, and durable effector activity. In this review, we organize metabolic barriers to ICB into a multiscale framework comprising four interconnected axes. The Local Resource Axis captures how nutrient competition, enzymatic depletion, lipid dysregulation, suppressive metabolites, and ionic stress reshape the tumor microenvironment. The Organelle Axis examines mitochondrial dysfunction, endoplasmic reticulum stress, and intercellular mitochondrial transfer as determinants of T-cell functional recovery. The Spatial Axis addresses stromal, vascular, and organ-specific immune-metabolic niches that regulate immune access and site-specific resistance. The Systemic Axis integrates host metabolic and temporal states, including obesity, cachexia, microbial ecology, and circadian organization. Across these axes, metabolic constraints impair T-cell receptor (TCR) signaling, biosynthesis, redox homeostasis, organelle fitness, tissue infiltration, and host immune reserve, while also reducing malignant-cell susceptibility to immune-mediated killing. We further discuss therapeutic implications through a clinical-readiness and chrono-metabolic scheduling framework that distinguishes practice-ready vascular-targeted combinations from trial-prioritized or investigational dietary, microbiome-directed, metabolite-targeted, and engineered T-cell strategies. This evidence-calibrated perspective reframes tumor immunometabolism not as a static catalogue of targets, but as a set of biologically timed and compartment-specific constraints that determine the conditions under which ICB can achieve durable immune control.