Metabolic Barriers to Cancer Immunotherapy: Multiscale Mechanisms from Organelle Dysfunction to Organ-Specific Constraints.
6 affiliations
- 1Division of Hepato-Pancreato-Biliary Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science & Technology, Wuhan, Hubei 430030, China.
- 2Key Laboratory of Organ Transplantation, Ministry of Education; NHC Key Laboratory of Organ Transplantation; Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Wuhan, China.
- 3Hubei Key Laboratory of Hepato-Pancreato-Biliary Diseases, Wuhan, Hubei 430030, China.
- 4Clinical Medicine Research Centre for Hepatic Surgery of Hubei Province, Hubei 430030, China.
- 5Clinical Medicine Research Centre for Pancreatic Surgery of Hubei Province, Hubei 430030, China.
- 6Department of Breast and Thyroid Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Abstract
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.
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BibTeX
@article{gui2026metabolic,
title = {{Metabolic Barriers to Cancer Immunotherapy: Multiscale Mechanisms from Organelle Dysfunction to Organ-Specific Constraints.}},
author = {Zichen Gui and Xiaoyin Yuan and Xiaoping Chen and Qibo Huang and Bixiang Zhang and Junnan Liang},
journal = {International journal of biological sciences},
year = {2026},
month = sep,
doi = {10.7150/ijbs.137618},
url = {https://europepmc.org/article/MED/42910256},
note = {CC BY},
}
RIS
TY - JOUR
TI - Metabolic Barriers to Cancer Immunotherapy: Multiscale Mechanisms from Organelle Dysfunction to Organ-Specific Constraints.
AU - Zichen Gui
AU - Xiaoyin Yuan
AU - Xiaoping Chen
AU - Qibo Huang
AU - Bixiang Zhang
AU - Junnan Liang
PY - 2026
DA - 2026/09/24
JO - International journal of biological sciences
DO - 10.7150/ijbs.137618
UR - https://europepmc.org/article/MED/42910256
AB - 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.
SN - 1449-2288
ER -