The importance of tumor microenvironment modulations in the progression of pancreatic intraductal papillary mucinous neoplasms - Invited commentary

Sep 23, 2026

Intraductal papillary mucinous neoplasms (IPMNs) of the pancreas are common macroscopic precursors of pancreatic cancer, often remaining indolent despite low-grade dysplasia. A subgroup progresses to invasive carcinoma through stepwise accumulation of genomic alterations and concurrent remodeling of the tumor microenvironment (TME). The commentary highlights an immunosuppressive shift during progression, including depletion of cytotoxic T cells, increased immune checkpoint expression (PD-L1, VISTA), and greater macrophage density. These TME changes support therapeutic strategies targeting TME modulation for cancer interception.

LanguageEnglish

CategoryHealthcare

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Pages4

Reading Time10 min

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Abstract

Commentary

Precancerous lesions of pancreatic ductal adenocarcinoma

TME remodeling across PanIN and IPMN progression

Immunosuppressive TME features and implications

Journal of Pathology J Pathol October 2025; 267: 126–129 Published online 30 July 2025 in Wiley Online Library (wi[leyonlinelibrary.com](leyonlinelibrary.com) DOI: 10.1002/path.6460)[)](leyonlinelibrary.com) DOI: 10.1002/path.6460)[ DOI:](leyonlinelibrary.com) DOI: 10.1002/path.6460)[ 10.1002/path.6460](leyonlinelibrary.com) DOI: 10.1002/path.6460) INVITED COMMENTARY The importance of tumor microenvironment modulations in the progression of pancreatic intraductal papillary mucinous neoplasms† Antonio Pea 1 and Claudio Luchini2,3* 1 Department of General and Pancreatic Surgery-The Pancreas Institute, Verona University Hospital Trust, Verona, Italy 2 Department of Diagnostics and Public Health, Section of Pathology, University of Verona, Verona, Italy 3 ARC-Net Research Center, University of Verona, Verona, Italy *Correspondence to: C Luchini, Department of Diagnostics and Public Health, Section of Pathology, and ARC-Net Research Center, University of Verona, Piazzale Scuro, 10, 37134, Verona, Italy. E-mail: [claudio.luchini@univr.it](claudio.luchini@univr.it) †Invited commentary for Jamouss et al. Tumor immune microenvironment alterations associated with progression in human intraductal papillary mucinous neoplasms. J Pathol 2025; 266: 40–50. Abstract Intraductal papillary mucinous neoplasms (IPMNs) of the pancreas have attracted substantial attention since they represent the most prevalent macroscopic precursor of pancreatic cancer. Most lesions show an epithelium with lowgrade dysplasia and will remain indolent and unknown to the patient. Notably, a subgroup of IPMNs will progress to invasive cancer through a stepwise process characterized by the accumulation of speciﬁc genomic alterations and concomitant modiﬁcations of the tumor microenvironment (TME). The manuscript of Jamouss et al, recently published in The Journal of Pathology, expands the current knowledge on TME dynamics in IPMNs. The neoplastic progression of IPMNs is paralleled by a shift toward an immunosuppressive TME, with depletion of cytotoxic T cells, elevated expression of immune checkpoint molecules, including PD-L1 and VISTA, and increased density of macrophages. Overall, TME modiﬁcations are crucial in the progression of pancreatic IPMNs, calling for potential therapeutic strategies focused on TME modulations for cancer interception. © 2025 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland. Keywords: tumor microenvironment; immune evasion; intraductal papillary mucinous neoplasm; pancreatic ductal adenocarcinoma Received 16 June 2025; Accepted 7 July 2025 Conﬂict of interest statement: CL reports honoraria from Astellas (consulting, steering committee), Bayer, MSD, and Medica s.r.l. (consulting and speaker bureau). AP reported no potential conﬂicts of interest. Commentary The study of precursors to pancreatic ductal adenocarcinoma (PDAC) represents a critical opportunity for investigating the complex mechanisms involved in pancreatic oncogenesis. In this scenario, pancreatic intraepithelial neoplasia (PanIN) and intraductal papillary mucinous neoplasm (IPMN) are the most extensively studied precancerous lesions of PDAC. A wealth of literature has elucidated the genomic alterations that drive malignant transformation in these precursors. More recently, a growing research focus has been tumor microenvironment (TME) modiﬁcations and their contribution to pancreatic oncogenesis in both PanINs and IPMNs. PanINs are microscopic precursors and show an immunosuppressive TME, which includes myeloid-derived suppressor cells, regulatory T cells, and tumor-associated macrophages (TAMs) [1] . A complex interplay between regulatory T cells and other immune cells in the TME, such as CD11c+ dendritic cells, results in the depletion of cytotoxic CD8+ T cells, supporting PanIN progression to invasive cancer [2] . Regulatory T cells are foun

FAQs

What makes intraductal papillary mucinous neoplasms (IPMNs) important for pancreatic cancer progression?

IPMNs are prevalent macroscopic precursors of pancreatic cancer. While most remain indolent, a subset progresses stepwise to invasive carcinoma alongside changes in the tumor microenvironment.

How does the tumor microenvironment (TME) change as IPMNs progress?

Progression is accompanied by a shift toward an immunosuppressive TME, including depletion of cytotoxic T cells, higher expression of immune checkpoint molecules such as PD-L1 and VISTA, and increased macrophage density.

Why do the authors emphasize TME-focused therapeutic strategies?

Because TME modifications are critical in IPMN progression, targeting TME modulation could help intercept cancer development rather than focusing only on tumor-intrinsic changes.

Sep 23, 2026

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