IL-1β+ macrophages fuel pathogenic inflammation in pancreatic cancer

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is a lethal disease with high resistance to therapies¹. Inflammatory and immunomodulatory signals co-exist in the pancreatic tumour microenvironment, leading to dysregulated repair and cytotoxic responses. Tumour-associated macrophages (TAMs) have key roles in PDAC², but their diversity has prevented therapeutic exploitation. Here we combined single-cell and spatial genomics with functional experiments to unravel macrophage functions in pancreatic cancer. We uncovered an inflammatory loop between tumour cells and interleukin-1β (IL-1β)-expressing TAMs, a subset of macrophages elicited by a local synergy between prostaglandin E₂ (PGE₂) and tumour necrosis factor (TNF). Physical proximity with IL-1β⁺ TAMs was associated with inflammatory reprogramming and acquisition of pathogenic properties by a subset of PDAC cells. This occurrence was an early event in pancreatic tumorigenesis and led to persistent transcriptional changes associated with disease progression and poor outcomes for patients. Blocking PGE₂ or IL-1β activity elicited TAM reprogramming and antagonized tumour cell-intrinsic and -extrinsic inflammation, leading to PDAC control in vivo. Targeting the PGE₂-IL-1β axis may enable preventive or therapeutic strategies for reprogramming of immune dynamics in pancreatic cancer.