HSPA1A promotes immune-evasive colorectal liver metastasis through post-transcriptional stabilization of APP mRNA.

Authors

Ying Wan, Zhifei Cao, Shanshan Shen, Ruidong Zuo, Ruiqiu Zhu, Lu Wu, Yuntian Shen, Yaqun Zhu, Qiliang Peng

Published in

International immunopharmacology. Volume 189. Pages 117412. Sep 12, 2026. Epub Sep 12, 2026.

Abstract

Colorectal cancer (CRC) liver metastasis remains a major clinical challenge, particularly in microsatellite-stable tumors that respond poorly to immune checkpoint blockade. Whether tumor cell-intrinsic stress programs actively promote immune evasion during hepatic colonization remains incompletely understood. Here, we integrated single-cell RNA sequencing analysis of paired primary CRC and liver metastases with in vivo liver metastasis models, HSPA1A loss- and gain-of-function assays, RNA-protein interaction assays, T cell co-culture experiments, and αPD-L1 treatment studies to investigate the role and mechanism of HSPA1A. HSPA1A was enriched in a metastasis-associated tumor cell state, and high HSPA1A expression was associated with poor survival and metastatic progression. Functionally, HSPA1A silencing markedly reduced hepatic metastatic burden in vivo without increasing tumor cell invasiveness or inducing epithelial-mesenchymal transition, suggesting a role in microenvironmental adaptation rather than intrinsic motility. Mechanistically, HSPA1A bound an AU-rich element within the APP mRNA 3' untranslated region, stabilized APP transcripts, and increased APP protein expression. HSPA1A depletion enhanced Th17-like CD4+ T cell responses, whereas APP overexpression attenuated this immune phenotype. Moreover, HSPA1A depletion improved the response to αPD-L1 therapy, prolonging survival and further suppressing liver metastatic burden. Collectively, these preclinical findings suggest that the HSPA1A-APP axis links tumor cell stress adaptation to immune-evasive hepatic colonization and may provide a mechanistic basis for improving immunotherapy responses in colorectal liver metastasis.

PMID:
42731467
Bibliographic data and abstract were imported from PubMed on 13 Sep 2026.

Read full publication at:
Please sign in to see all details.

Stats

1-terrible, 9-excellent. How would you rate this publication? Sign in in to submit your rating.

Post a comment

You need to be signed in to post comments. You can sign in here.

Comments

There are no comments yet.