Proteostasis Sustains T Cell Differentiation Potential and Tumor-Infiltrating Lymphocyte Function
Researchers from UC San Diego, in collaboration with LJI, UAMS, and the Allen Institute for Immunology, have shown that proteostasis is a key factor of T cell differentiation potential and antitumor function. Published in Cell, the authors demonstrate a shared expression of proteostasis-related genes between tissue-resident memory T cells (TRM) and progenitor-exhausted T cells (TPEX), with terminally exhausted T cells (TEX) losing this program, accumulating unfolded proteins, and becoming functionally impaired. Restoring proteostasis through enforced expression of the E3 ubiquitin ligases neuralized E3 ubiquitin protein ligase 3 (NEURL3), RING finger protein 149 (RNF149), or WD repeat and suppressor of cytokine signaling (SOCS) box-containing 1 (WSB1) preserved stem-like TCF1+ T cell populations, improved cytokine function, and enhanced tumor control, pinpointing protein-quality control as a therapeutically targetable axis in T cell exhaustion.
Persistent tumor or viral antigen exposure can drive CD8+ T cell exhaustion, limiting the ability of tumor-infiltrating lymphocytes (TILs) to control tumor growth. This process produces a spectrum from TCF1+ progenitor-exhausted cells to terminally exhausted cells with impaired metabolism, checkpoint-receptor expression, and reduced effector function. The authors focused on protein homeostasis, an underexplored feature of T cell exhaustion, and hypothesized that TRM- and TPEX-associated E3 ubiquitin ligases sustain T cell function by promoting regulated protein turnover and preventing unfolded-protein stress. They tested this using integrated transcriptomic and proteomic profiling across tumor and infection models, followed by gain- and loss-of-function studies of candidate ligases and evaluation in adoptive T cell therapy settings.
Functionally, NEURL3, RNF149, and WSB1 overexpression increased transferred T cell accumulation, TCF1+ frequency, and IFNγ+TNF+ polyfunctionality in tumors, whereas knockout reduced TIL abundance. In MC38-GP33 tumors, complete tumor regressions increased from 1/9 mice receiving empty-vector P14 T cells to 7/9 mice receiving NEURL3-overexpressing P14 T cells. Similar improvements were observed with RNF149-overexpressing P14 cells, from 5/10 to 8/12, and WSB1-overexpressing P14 cells, from 2/15 to 9/15, accompanied by significant survival benefits. TEX retained functional proteasomes but showed increased K48-linked ubiquitin and unfolded-protein-response signatures, with ligase overexpression rescuing this proteotoxic stress. In human melanoma, RNF149 and WSB1 expression correlated with checkpoint-blockade response, and triple-ligase T cells plus anti-PD-1 improved tumor control in mice, placing proteostasis alongside checkpoint and metabolic programming as a major determinant of durable T cell immunotherapy.
Reference:
Scharping NE, Ge X, Matias MI, et al. Proteostasis sustains T cell differentiation potential and tumor-infiltrating lymphocyte function. Cell. 2026;189(10):2857-2874.e31. http:doi.org/10.1016/j.cell.2026.02.019