Adaptive IRE1 Signaling Elicits T Cell Metabolic Remodeling and Tumor Control

The efficacy of cancer immunotherapies is limited by the metabolic instability of the tumor microenvironment (TME) that disables T cell antitumor immunity. Metabolic imbalances within the TME are sensed and responded to by stress sensors of the endoplasmic reticulum (ER) unfolded protein response (UPR). The UPR comprises three integrated signaling pathways harboring both adaptive and deleterious phases based on the extent and duration of cell stress. Here, we elucidate the differential contributions of adaptive and deleterious signaling downstream of the UPR IRE1 pathway in T cell-regulated tumor control. T cells in murine and patient cancers experience persistent ER stress, leading to hyperactive IRE1 signaling that limits tumor control. However, amplifying the adaptive arm of the IRE1 UPR serves to eliminate mitochondrial toxicity and protect T cells from chronic ER stress, yielding robust tumor engraftment and long-term tumor immunity. Our findings establish the UPR’s essential protective role in antitumor immunity. ### Competing Interest Statement R.L.W. is an inventor on a patent describing IRE1/XBP1s-activating compounds, including IXA4, and is a scientific advisory board member and shareholder in Protego Biopharma. The authors declare no other competing interests.