# Multimodal profiling of pancreatic cancer reveals a TIMP-1-dominated secretory profile determining pro-tumor immunoinstruction in human cancers

## TL;DR

The study identifies a secretory profile in pancreatic cancer that promotes tumor growth by suppressing immune cells, with TIMP-1 as a key driver and potential therapeutic target.

## Contribution

The study introduces a novel cancer-immunoinstructive secretory signature (CISS) dominated by TIMP-1, linking it to immunosuppression and therapeutic targeting in pancreatic cancer.

## Key findings

- CISS is a secretory profile linked to poor prognosis and immunosuppressive tumor environments across cancers.
- TIMP-1 is central to CISS in pancreatic cancer, suppressing natural killer cell activity and mTOR signaling.
- TIMP-1/CISS can be targeted in pre-clinical pancreatic cancer using approved drugs trametinib and nintedanib.

## 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.

•A secretory profile (CISS) links malignant evolution to immunosuppression in cancer•In PDAC, CISS arises in pre-malignancy and culminates in TIMP-1hi basal-like cancer•PDAC-cell-mediated NK cell suppression is TIMP-1-dependent•TIMP1/CISS identify high-risk patients and prove targetable in pre-clinical PDAC

A secretory profile (CISS) links malignant evolution to immunosuppression in cancer

In PDAC, CISS arises in pre-malignancy and culminates in TIMP-1hi basal-like cancer

PDAC-cell-mediated NK cell suppression is TIMP-1-dependent

TIMP1/CISS identify high-risk patients and prove targetable in pre-clinical PDAC

By multiomic profiling across human cancers, Frädrich et al. discover a secretory profile linking malignant evolution to immunosuppression and poor patient survival. In pancreatic cancer, this profile is shaped by TIMP-1-dependent NK cell suppression and proves targetable through clinically approved kinase inhibitors, highlighting exploitable prognostic and therapeutic potential.