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Endoplasmic reticulum stress responses in anticancer immunity

Nature Reviews Cancer volume 25, pages 684–702 (2025)Cite this article

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Abstract

The endoplasmic reticulum (ER) has a central role in processes essential for mounting effective and durable antitumour immunity; this includes regulating protein synthesis, folding, modification and trafficking in immune cells. However, the tumour microenvironment imposes hostile conditions that disrupt ER homeostasis in both malignant and infiltrating immune cells, leading to chronic activation of the unfolded protein response (UPR). Dysregulated ER stress responses have emerged as critical modulators of cancer progression and immune escape, influencing the initiation, development and maintenance of antitumour immunity. In this Review, we examine how tumour-induced ER stress reshapes the functional landscape of immune cells within the tumour microenvironment. We highlight recent discoveries demonstrating how ER stress curtails endogenous antitumour immunity and reduces the efficacy of immunotherapies. Furthermore, we underscore novel therapeutic strategies targeting ER stress sensors or UPR components to restore immune function and enhance cancer immunotherapy outcomes. Together, this provides a comprehensive overview of the interplay between ER stress responses and antitumour immunity, emphasizing the potential of UPR-targeted interventions to improve immune control of cancer.

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Fig. 1: Metabolic stressors disturbing ER homeostasis in the TME.
Fig. 2: Immunomodulatory effects of ER stress in cancer cells.
Fig. 3: ER stress responses in intratumoural immune cells.

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Acknowledgements

We apologize to colleagues whose work could not be included in this review due to space limitations. We are grateful to all past and present members of the Rodriguez and Cubillos-Ruiz laboratories for their scientific contributions. ER stress-related research in the Rodriguez lab has been supported by NIH grants R01-CA233512, R01-CA262121, R01-CA27303 and P01-CA250984 Project #4 to P.C.R. ER stress-related research in the Cubillos-Ruiz lab has been supported by NIH R01 grants NS114653, CA271619 and CA282072; US Department of Defense grants W81XWH-16-1-0438, W81XWH-21-1-0478 and W81XWH-22-OCRP-IIRA; The Mark Foundation for Cancer Research, The Pershing Square Sohn Cancer Research Alliance, AACR-Stand Up to Cancer, The Cancer Research Institute, and the Ovarian Cancer Research Alliance. S.-M.H. was supported by the AACR-Bristol Myers Squibb Immuno-Oncology Research Fellowship.

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Author notes

  1. These authors contributed equally: Sung-Min Hwang, Shiun Chang.

Authors and Affiliations

  1. Department of Obstetrics and Gynecology, Weill Cornell Medicine, New York, NY, USA

    Sung-Min Hwang & Juan R. Cubillos-Ruiz

  2. Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA

    Sung-Min Hwang & Juan R. Cubillos-Ruiz

  3. Department of Immunology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA

    Shiun Chang & Paulo C. Rodriguez

  4. Weill Cornell Graduate School of Medical Sciences, New York, NY, USA

    Juan R. Cubillos-Ruiz

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  1. Sung-Min Hwang
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  4. Juan R. Cubillos-Ruiz
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The authors contributed equally to all aspects of the article.

Corresponding authors

Correspondence to Paulo C. Rodriguez or Juan R. Cubillos-Ruiz.

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Competing interests

P.C.R. and J.R.C.-R. hold patents on the targeting of ER stress responses for the treatment of disease, as well as on the use of immune modulators for cancer therapy. J.R.C.-R. is a scientific consultant for Autoimmunity Biologic Solutions, Inc., and Emerald Bioventures, LLC, and holds stock options in Vescor Therapeutics.

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Nature Reviews Cancer thanks Eric Chevet, Jessica Thaxton who co-reviewed with Annaleigh Powe and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Glossary

Autophagy

A conserved lysosomal degradation pathway that recycles cellular components, regulating metabolism, stress adaptation and immune responses in health and disease.

Immunogenic cell death

(ICD). A regulated form of cell death that elicits an adaptive immune response by releasing damage-associated molecular patterns and promoting antigen presentation.

Major histocompatibility complex

(MHC). A group of cell surface molecules responsible for antigen presentation to T cells, enabling immune recognition and activation in both innate and adaptive immunity.

Paraptosis

A caspase-independent, non-apoptotic form of programmed cell death distinguished by cytoplasmic vacuolization and mitochondrial swelling, often linked to ER stress and protein aggregation.

Polymorphonuclear myeloid-derived suppressor cells

(PMN-MDSCs). A subset of immunosuppressive myeloid cells with neutrophil-like features that inhibit T cell activation and promote immune evasion within the tumour microenvironment.

Pyroptosis

A lytic, pro-inflammatory form of programmed cell death triggered by inflammasome activation, characterized by gasdermin-mediated membrane pore formation and cytokine release.

Tertiary lymphoid structures

(TLSs). Ectopic lymphoid aggregates that develop in non-lymphoid tissues during chronic inflammation or cancer, serving as local hubs for immune activation and adaptive responses.

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Hwang, SM., Chang, S., Rodriguez, P.C. et al. Endoplasmic reticulum stress responses in anticancer immunity. Nat Rev Cancer 25, 684–702 (2025). https://doi.org/10.1038/s41568-025-00836-5

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