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A Fluorescence-based Protocol for Preliminary Screening of Protein Synthesis Inhibitors from Natural Sources
10:24

A Fluorescence-based Protocol for Preliminary Screening of Protein Synthesis Inhibitors from Natural Sources

Published on: January 27, 2026

Targeting the unfolded protein response in cancer: mechanisms, small-molecule inhibitors, and translational

Meizhen Lin1,2, Zhijie Li1,2

  • 1Department of Pediatrics, Shengjing Hospital of China Medical University, Shenyang, China.

Frontiers in Immunology
|August 14, 2026
PubMed

Insights

Endoplasmic reticulum (ER) stress and the unfolded protein response (UPR) play dual roles in cancer, promoting growth but also offering therapeutic targets. Targeting UPR pathways presents a promising strategy for novel cancer treatments.

Area of Science:

  • Molecular Biology
  • Cancer Biology
  • Immunology

Background:

  • Endoplasmic reticulum (ER) stress arises from misfolded proteins, activating the unfolded protein response (UPR) to maintain protein homeostasis.
  • Dysregulated ER stress and UPR are implicated in cancer progression, immune evasion, and antitumor immunity.
  • The UPR involves three sensors: PERK, IRE1α, and ATF6, coordinating cellular responses.

Purpose of the Study:

  • To review mechanistic insights into UPR-driven tumor progression, immune regulation, and immunotherapy resistance.
  • To explore advances in small-molecule inhibitors targeting UPR pathways for cancer treatment.
  • To critically evaluate the therapeutic potential and translational challenges of UPR-targeted cancer therapies.

Main Methods:

  • Literature review integrating mechanistic insights and therapeutic strategies.
  • Analysis of UPR pathway crosstalk, immune regulation, and immunotherapy resistance.
  • Evaluation of small-molecule inhibitors and chemical chaperones targeting UPR sensors (PERK, IRE1α, ATF6).

Main Results:

  • ER stress promotes malignancy, tumor growth, and metastasis, but excessive UPR activation can induce cell death.
  • Targeting IRE1α, PERK, and ATF6 pathways offers distinct anticancer strategies, influencing chemoresistance and immune escape.
  • Chemical chaperones demonstrate context-dependent cytoprotective and antitumor effects.

Conclusions:

  • Pharmacological targeting of the UPR is a promising anticancer strategy due to its context-dependent duality.
  • Understanding UPR pathway crosstalk and immune modulation is crucial for effective cancer therapy.
  • Translational challenges remain in developing and applying UPR-targeted therapies in clinical settings.
Keywords:
ATF6IRE1αPERKcancer therapychemical chaperonesunfolded protein response

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