Tumor-infiltrating immature innate lymphoid cells in colorectal cancer are biased toward ILC1/tissue-resident NK cell differentiation
- Anne Marchalot
- Malin Ljunggren
- Christopher Stamper
- Whitney Weigel
- Christopher Andrew Tibbitt
- Isabel Meininger
- Ram Vinay Pandey
- Miriam Franklin
- John Washington Bassett
- Lorenz Wirth
- Ali Kiasat
- Anders Hansson Elliot
- Carl Kördel
- Emma Rosander
- Henrik Iversen
- Madelene Ahlberg
- Mirna Abraham Nordling
- Petri Rantanen
- Richard Marsk
- Stefan Carlens
- Ulf O. Gustafsson
- Ulrik Lindforss
- Gabriella Jansson-Palmer
- Caroline Nordenvall
- Jenny Mjösberg
2026-03-27
Peritoneal metastases (PM) occur in 10% of patients with colorectal cancer (CRC) and are linked to poor outcomes. Although dysregulated innate lymphoid cells (ILC) have been described in CRC, their function in CRC-PM remains unclear. Here, we analyze tumor samples from CRC and CRC-PM patients using single-cell RNA sequencing (11 patients), flow cytometry (8 patients) and differentiation assays (24 patients). Healthy colon, primary CRC and CRC-PM tumors are infiltrated by heterogeneous populations of ILC3, ILC2, ILC1, tissue resident (tr)NK cells and conventional (c)NK cells. Compared to healthy colons, primary CRC and CRC-PM tumors are depleted of ILC3 but enriched for ILC1, trNK cells and cNK cells. CRC and CRC-PM tumors harbor two immature ILC populations, early NK and naïve (n)ILC, with nILCs being transcriptionally skewed toward ILC1 and trNK cells. Indeed, co-culture of isolated nILCs with OP9-DL1 cells induces intratumoral nILC differentiation into ILC1/trNK-like cells. These findings help understand the immune pathogenesis of CRC and CRC-PM and provide insights for future ILC1 and NK cell-based therapies.