T-Cell Exhaustion in the Tumor Microenvironment: Subcellular Dysfunction, Pan-Cancer Characteristics, and Therapeutic Interventions.

Although immune checkpoint blockade (ICB) therapy has profoundly reshaped the landscape of oncology, T-cell exhaustion (Tex) remains a core challenge in immunotherapy for solid tumors. Current research predominantly focuses on signal transduction and epigenetic regulation, whereas the adaptive alterations and dysfunction of subcellular organelles within T cells under the stress of the tumor microenvironment (TME) have not been systematically elucidated. This review proposes that suborganellar dysfunction serves as a key functional link in the progression of Tex. We systematically explore the role of dysregulated organelle interaction networks in this exhaustion, including mitochondrial dynamics and metabolic perturbations, aberrant endoplasmic reticulum (ER) stress responses, and mechanical stress-induced nuclear damage, elucidating how these alterations form a self-sustaining vicious cycle. Furthermore, we summarize the heterogeneity and commonalities of T-cell subcellular dysfunction across various solid tumors, such as oxidative stress-mediated mitochondrial damage in lung cancer, aberrant lipid metabolism-induced ER stress in hepatocellular carcinoma, and the suppression of lysosomal function in highly glycolytic tumors. Finally, we review emerging interventional strategies targeting these organelle checkpoints, such as nanomaterial-based mitochondrial protection, delivery systems modulating ER homeostasis, and stimuli-responsive matrix regulation technologies, aiming to provide novel perspectives for enhancing the anti-tumor efficacy of T cells via subcellular engineering approaches.