Multimodal profiling of pancreatic cancer reveals a TIMP-1-dominated secretory profile determining pro-tumor immunoinstruction in human cancers.
basic_science · Level V
Where this comes from
- Record sourced from PubMed, PMID 41564862.
- Also identified by DOI 10.1016/j.xcrm.2025.102546 and PMC identifier 12866174.
- Licence recorded as CC BY.
- The licence permits redistribution, so the abstract is shown in full and the full text is available from the publisher.
Abstract
The immunosuppressive tumor microenvironment (TME) fosters cancer progression, yet overarching determinants of cancer-borne immunoinstruction remain ill-defined. By multimodal integration of single-nucleus and bulk transcriptomics, proteomics, functional approaches, and clinical parameters, we discover a cancer-immunoinstructive secretory signature (CISS) across multiple human cancers-a set of inflammatory proteins correlated with poor prognosis and pro-tumorigenic TMEs. In pancreatic cancer (PC), CISS arises in pre-malignant epithelium, intensifies along transformation toward most malignant basal-like PC, and particularly correlates with suppressed natural killer (NK) cell activity. The CISS is quantitatively dominated by tissue inhibitor of metalloproteinases (TIMP)-1, most prevalent in TIMP-1<sup>hi</sup>/CISS<sup>hi</sup> basal-like PC, and causal for PC-cell-mediated NK cell suppression, reflected by impaired cytotoxicity, interleukin-2 (IL-2) responses, and mammalian target of rapamycin (mTOR) signaling. In pre-clinical PC, TIMP-1/CISS proves targetable through combined inhibition of upstream kinases with clinically approved drugs trametinib and nintedanib. Collectively, CISS represents a ubiquitous signature of pro-tumor immunoinstruction with actionable diagnostic and therapeutic potential across human cancers.
Medical subject headings
- Tissue Inhibitor of Metalloproteinase-1
- Pancreatic Neoplasms