714 Tumor stress rewires endoplasmic reticulum architecture to enforce T cell dysfunction in cancer
Year: 2026
Type: conference-abstract
Abstract: Background The tumor microenvironment imposes chronic endoplasmic reticulum (ER) stress that drives CD8 + T cell dysfunction, yet how these signals are integrated to dictate cell fate remains unclear. We investigated whether the dynamic architecture of the ER was altered in intratumoral CD8+ T cells, serving as a central regulatory layer linking tumor-derived stress to T cell function in cancer.Methods We used 3D projections of confocal microscopy, spectral flow cytometry, and scRNA-seq to define the dynamic architecture of the ER in intratumoral CD8 + T cells from patients with cancer and mouse models. We used antigen-specific virus and tumor mouse models paired with multiplex imaging of hypoxic regions of tumors to define tumor microenvironment conditions that exacerbate ER distention. CD8creIRE1f/f and CD8crePERKf/f mouse models were used to assess the contribution of ER stress sensors to ER dysmorphia. Unique CD8creCKAP4f/f mice were generated and paired with metabolomics, proteomics, protein translation assays, spatial localization analysis, and in vivo tumor modeling to study the contribution of ER sheet proliferation to T cell dysfunction in cancer. Spatial transcriptomics was performed on samples from PD-1 inhibitor responsive vs. non-responsive HNSCC patients (ClinicalTrials.gov NCT03021993).Results We identify ER architecture as a central regulatory layer linking tumor-derived stress to T cell dysfunction in cancer. Hypoxia-driven activation of ER stress pathways induces the ER sheet protein cytoskeleton-associated protein 4 (CKAP4), triggering pathological ER expansion in tumor-infiltrating T cells. This structural remodeling suppresses T cell infiltration to hypoxic tumor regions and limits metabolic plasticity and healthy proteostasis in intratumoral T cells, together impeding cytotoxicity in cancers. Genetic ablation of CKAP4 restores ER architecture and supports T cell infiltration to hypoxic zones of tumors while simultaneously restoring metabolic and protein homeostasis that support tumor control. In human cancers, CKAP4 expression and ER sheet-associated programs are enriched in T cell–infiltrated tumor regions of immune checkpoint inhibitor non-responders.Conclusions These findings establish ER structural remodeling as a mechanism by which tumor stress is encoded into T cell fate, positioning organelle architecture as a determinant of immune cell spatial localization and function in cancer ( figure 1).Trial Registration ClinicalTrials.gov NCT03021993.Ethics Approval Patients undergoing surgical removal of solid cancers granted informed written consent under The University of North Carolina at Chapel Hill (UNC-CH) surgical consent form. This work was determined to be exempt by the UNC-CH Institutional Review Board (IRB) under protocol LCCC9001. All animal experiments and breeding were performed in accordance with protocols 21-225, 24-163, 21-228, and 24-195 approved by the Institutional Animal Care and Use Committee (IACUC) at the University of North Carolina at Chapel Hill.Abstract 714 Figure 1
Authors: Genevieve T Clutton, Andrew S Kennedy, Elizabeth G Hunt, Jessica W Hem, Coral Del Mar Alicea Pauneto, Brian P Riesenberg, Jarred M Green, Katie E Hurst, Ryan S Hagle, Lindsay A Sheft, Xin Zhou, Robert J Esther, Gabriella Simal, Hannah M Knochelmann, Chrystal M Paulos, David Neskey, Mia Wallace, Juan R Cubillos-Ruiz, Barbara Savoldo, Gianpietro Dotti, Shelton Earp, Sumita Trivedi, Yusha Liu, William D Green, Justin Milner, Joseph C Genereux, Wendy C Salmon, R Luke Wiseman, Jessica E Thaxton
Language: English
Subfield: Cell Biology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $2,490
OpenAlex ID: W7225319040