Hypoxic stress granules trigger immunogenic dormancy in lung cancer
Matthew G Smith1,2, Alexis Rebecca Ramos1,3, Heena Panchal1
1Department of Microbiology and Immunology, Carver College of Medicine, University of Iowa, Iowa City, IA.
Biorxiv : the Preprint Server for Biology
|February 27, 2026
Summary
Tumor hypoxia blocks the MHC class I antigen processing and presentation pathway (C1APP), impairing cancer cell immunity. This immune escape mechanism involves stress granules and is reversible with 5-azacytidine.
Area of Science:
- Immunology
- Cancer Biology
- Molecular Biology
Background:
- The MHC class I antigen processing and presentation pathway (C1APP) is crucial for cytotoxic immunity against epithelial cancers.
- Impaired C1APP induction is linked to poor disease outcomes and resistance to immunotherapy.
- Tumor cells require C1APP to present antigens and neoantigens to cytotoxic T cells.
Purpose of the Study:
- To investigate the impact of physiological hypoxia on C1APP induction in cancer cells.
- To elucidate the molecular mechanisms by which hypoxia affects C1APP.
- To explore potential therapeutic strategies to overcome hypoxia-induced immune evasion.
Main Methods:
- Assessing C1APP component induction under hypoxic conditions in cancer cell lines (e.g., A549).
- Analyzing immunopeptide presentation using mass spectrometry.
- Investigating the role of hypoxia-inducible factors (HIFs), protein degradation, and autophagy.
- Examining mRNA translation and stress granule formation.
- Evaluating the effect of 5-azacytidine on C1APP induction and immunopeptide presentation.
- Correlating IP expression with hypoxic regions in human NSCLC tumors.
Main Results:
- Physiological hypoxia blocks the induction of the immunoproteasome (IP) and other C1APP components in cancer cells, including NSCLC.
- Hypoxia impairs the presentation of over 73% of detectable immunopeptides, including tumor-associated antigens and neoantigens.
- This effect is independent of HIF-1α/HIF-2α signaling, protein degradation, or autophagy.
- Hypoxia induces translational arrest of C1APP mRNAs and their sequestration into stress granules.
- The observed effects are reversible with 5-azacytidine treatment.
- Immunoproteasome expression is notably absent in hypoxic tumor regions of human NSCLC.
Conclusions:
- Tumor hypoxia creates a state of "immunogenic dormancy" by inhibiting C1APP.
- Hypoxia-induced stress granules represent a novel mechanism of immune escape in cancer.
- Targeting stress granule formation or utilizing epitranscriptomic modifiers like 5-azacytidine may restore anti-tumor immunity in hypoxic tumors.
