Cell

Tumor microenvironment

Biology

Cancer

Endoplasmic reticulum

Unfolded protein response

Stromal cell

Immunology

Cell biology

Cancer research

Genetics

Reprogramming

Immune system

Cancer cell

Nature reviews. Cancer

Protein handling, modification and folding in the endoplasmic reticulum (ER) are tightly regulated processes that determine cell function, fate and survival. In several tumour types, diverse oncogenic, transcriptional and metabolic abnormalities cooperate to generate hostile microenvironments that disrupt ER homeostasis in malignant and stromal cells, as well as infiltrating leukocytes. These changes provoke a state of persistent ER stress that has been demonstrated to govern multiple pro-tumoural attributes in the cancer cell while dynamically reprogramming the function of innate and adaptive immune cells. Aberrant activation of ER stress sensors and their downstream signalling pathways have therefore emerged as key regulators of tumour growth and metastasis as well as response to chemotherapy, targeted therapies and immunotherapy. In this Review, we discuss the physiological inducers of ER stress in the tumour milieu, the interplay between oncogenic signalling and ER stress response pathways in the cancer cell and the profound immunomodulatory effects of sustained ER stress responses in tumours. The hostile microenvironment of the tumour can disrupt endoplasmic reticulum (ER) homeostasis in cancer cells and infiltrating immune cells to result in a state of ER stress. This Review discusses how ER stress can influence not only the pro-tumoural features of cancer cells but also reprogramme the function of innate and adaptive immune cells, creating vulnerabilities that could be targeted by emerging therapeutic strategies.

Endoplasmic reticulum stress signals in the tumour and its microenvironment