The Unfolded Protein Response as a Modulator of Cancer-Immune Cell Communication in the Tumour Microenvironment.

The tumour microenvironment (TME) comprises a dynamic network of structural, cellular, and signalling components that interact to influence tumour development. Immune cells play a key role in recognizing and eliminating cancer cells through detection of tumour-derived membrane and secreted proteins processed in the endoplasmic reticulum (ER). These ER-matured proteins on target cells act as critical communication signals, coordinating immune responses against tumour cells. However, during tumorigenesis, accumulation of unfolded or misfolded proteins in the ER of the cancer cells triggers the unfolded protein response (UPR), a transcriptional program that alleviates proteotoxic stress by reshaping the cancer cell proteome and secretome, thereby promoting survival. Activation of UPR disrupts intercellular communication and ultimately impairs immune-mediated tumour clearance. Understanding this crosstalk could inform the development of therapeutics targeting UPR-driven immune modulation. This review discusses how UPR-signalling modulates tumour-immune cell interactions within the TME.