Journal Article

DKFZ-2026-00167

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Multimodal profiling of pancreatic cancer reveals a TIMP-1-dominated secretory profile determining pro-tumor immunoinstruction in human cancers.

Frädrich, J. ; Reyes, C. M.DKFZ* ; Hendel, M. ; Brunner, V. ; Toledo, B. ; Manevski, D. ; Sommer, A. ; Häußler, D. ; Beck, D. ; Lucarelli, D. ; Martínez de Villareal, J. ; Halle, L. ; Kfuri-Rubens, R. ; Çifcibaşı, K. ; Hirschberger, A. ; Öllinger, R. ; Knolle, P. A. ; Steiger, K. ; Rad, R. ; Theis, F. J. ; Real, F. X. ; Bärthel, S.DKFZ* ; Böttcher, J. P. ; Saur, D.DKFZ* ; Demir, I. E.DKFZ* ; Krüger, A.

2026
Cell Press Cambridge, MA

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-1hi/CISShi 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.

Keyword(s): Humans (MeSH) ; Tissue Inhibitor of Metalloproteinase-1: metabolism (MeSH) ; Tissue Inhibitor of Metalloproteinase-1: genetics (MeSH) ; Pancreatic Neoplasms: immunology (MeSH) ; Pancreatic Neoplasms: pathology (MeSH) ; Pancreatic Neoplasms: genetics (MeSH) ; Pancreatic Neoplasms: metabolism (MeSH) ; Tumor Microenvironment: immunology (MeSH) ; Killer Cells, Natural: immunology (MeSH) ; Cell Line, Tumor (MeSH) ; Pyridones: pharmacology (MeSH) ; Signal Transduction (MeSH) ; TIMP-1 ; cancer heterogeneity ; cancer immunosuppression ; epithelial heterogeneity ; natural killer cells ; pan-cancer ; pancreatic cancer ; Tissue Inhibitor of Metalloproteinase-1 ; TIMP1 protein, human ; Pyridones

Note: #DKTKZFB26#

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Contributing Institute(s):

1. DKTK Koordinierungsstelle München (MU01)
2. DKTK MU Translationale Krebsforschung (MU05)

Research Program(s):

1. 899 - ohne Topic (POF4-899) (POF4-899)

Appears in the scientific report 2026

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Database coverage:
; ; ; Article Processing Charges ; BIOSIS Previews ; Biological Abstracts ; Clarivate Analytics Master Journal List ; Current Contents - Clinical Medicine ; Current Contents - Life Sciences ; DOAJ Seal ; Essential Science Indicators ; Fees ; IF >= 10 ; JCR ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection

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