Mechanism and intervention strategy of thymus atrophy in cancer immunotherapy.

Abstract

Thymic atrophy is a major determinant of T-cell dysfunction and immunosenescence, as it restricts de novo T-cell generation, reduces the T-cell receptor (TCR) repertoire, hastens peripheral T-cell aging, and disrupts central immune tolerance. It presents an enormous barrier to antitumor immune surveillance as well as current cancer immunotherapies such as immune checkpoint inhibitors (ICIs) and chimeric antigen receptor T-cell (CAR-T) therapy. In this review, we discuss how age, metabolic disorders, psychological stress, cancer pathology, and cancer-directed therapies converge upon thymic epithelial cells, stromal organization, and hematopoietic progenitor trafficking leading to structural and functional thymic decline. We then describe how thymopoiesis impairment reshapes tumor immunity and therapeutic responsiveness, and summarize noninvasive imaging methods for assessment of thymic health, and highlight new strategies for thymic regeneration or functional replacement through pharmacologic agents, cytokine and endocrine modulation, mRNA-based trophic factor delivery, cell replacement, tissue engineering, and thymus-centered CAR-T platforms. Despite significant translational challenges, rapid advances in thymic regeneration biology suggest that restoration of thymic function may be a rational host-directed approach to enhance the depth, duration, and safety of cancer immunotherapy.