Fig. 1: Irradiation-mediated alterations of T cells in the TME.

A RT increases the expression of tumor-associated antigen NY-ESO-1, which binds CRT and thus activates CD8⁺ T cells to secrete more IFN-γ. Irradiation induces cytoplasmic DNA, which is sensed by cGAS, generating the second messenger cGAMP, thereby activating the STING protein. STING has been shown to induce IFN-β production by recruiting TBK1 to activate IRF3. IFN-β acts in an autocrine manner on the IFNAR of T cells, inhibiting AKT activity and promoting TCF-1 expression, which maintains the T cell stem cell-like state. However, RT activates IRF1 to promote Serpinb9 gene expression, thereby blocking CD8⁺ T cell attack. On the other hand, irradiation induces tumor cells to secrete IFNs, working on the IFNAR to activate Serpinb9 gene expression through the JAK/STAT pathway. In addition, irradiation reduces MYC expression levels and downregulates GLUT1, HK2 and LDHA genes involved in glucose uptake and glycolysis of T cells through mTORC regulation. Treg cell transcription factor Foxp3 reprograms cellular metabolism by repressing MYC. RT elicits an increase in ROS, activates NFAT and subsequently promotes IL-2 production, thereby activating effector T cells. B RT increases CD62^-CD44⁺ effector memory T cells and CD62⁺CD44⁺ central memory T cells in the spleen. Irradiation augments activated CD25⁺CD8⁺ memory T cells, CD25⁺CD4⁺ memory T cells and ICOS⁺CD4⁺ effector memory T cells in peripheral blood. C RT combined with immunotherapy (αPD-1 and αCTLA-4) facilitates the differentiation of pre-exhausted Th1-like cells into intratumoral CD4⁺ Tex cells, during which exhaustion-related and cytotoxic genes are upregulated. D RT enhances the secretion of activin A from tumor cells. Activin A binds to the corresponding receptor ActRI/ActRII, activates the receptor kinase activity and phosphorylates the intracellular mediator SMAD2/3. SMAD2/3 translocates to the nucleus and binds to the CNS1 together with the NFAT. This promotes the transcription of Foxp3. Irradiation induces ROS production, which is reported to stabilize and accumulate SENP3, thereby mediating deSUMOylation of the transcription factor BACH2 and maintaining the immunosuppressive effects of Tregs. Solid lines represent anti-tumor effects and dashed lines represent pro-tumor effects.