CNPY2-orchestrated unfolded protein responses play redundant roles in regulating anti-tumor immunity of CD8 +T cells

Abstract Tumors evade immune surveillance by creating a hostile environment that impairs the functions of cells. Persistent perturbations including chronic antigen stimulation and metabolic challenges cause endoplasmic reticulum (ER) stress unfolded protein responses (UPR) in T CNPY2 is one key initiators UPR ER, but its roles cell activation persistence have not been reported. Herein, we found expressions other molecules pathways were upregulated both activated exhausted cells, indicating activation. However, genetic deletion Cnpy2 CD8 +T cells did result changes viability, proliferation, mitochondrial functions, translation rate under acute or vitro. Furthermore, no differences seen between wild-type CD8-specific knockout mice protection against multiple syngeneic tumor models colon (MC38 CT26), bladder (MB49), melanoma (YUMM1.7 B16-F10) breast tumors (4T1). Although from moderately more absence CNPY2, apparent impact was observed on +infiltration effector differentiation. Finally, mRNA profiling proteomic analysis, downstream signaling remained intact despite loss CNPY2. In summary, concluded persistent TCR microenvironment induce expression ablating alone failed to overcome UPR-mediated dysfunction, suggesting targeting UPRs need be considered improve cancer immunotherapy.