Hypoxic Tumor Microenvironment Targeting - Opportunities and Challenges for Pancreatic Cancer Immunotherapy

Sep 22, 2026

Pancreatic ductal adenocarcinoma remains highly lethal, driven by severe tumor hypoxia associated with desmoplasia, aberrant vasculature, and high interstitial pressure. Hypoxia stabilizes HIFs and reshapes the tumor microenvironment into a nutrient-poor, acidic state that promotes immune exclusion and suppression, contributing to poor responses to immune checkpoint inhibitors. The review analyzes hypoxia’s mechanistic role in immune evasion and summarizes therapeutic advances targeting hypoxia directly or indirectly, while discussing the need for hypoxia biomarkers and gene signatures to enable precision modulation.

LanguageEnglish

CategoryHealthcare

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Pages33

Reading Time1 h 23 min

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Review Hypoxic Tumor Microenvironment Targeting: Opportunities and Challenges for Pancreatic Cancer Immunotherapy Raefa Abou Khouzam 1, Shaima Salman 2, Jerome Thiery 3, Rania Faouzi Zaarour 1, Visar Vela 4, Perparim Limani 5,6, Bassam Janji 7 and Salem Chouaib 1,3, * Academic Editor: Yuji Arai Received: 23 March 2026 Revised: 22 April 2026 Accepted: 23 April 2026 Published: 27 April 2026 Correction Statement: This article has been republished with a minor change. The change does not affect the scientific content of the article and further details are available within the backmatter of the website version of this article. Copyright: © 2026 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license. 1 Thumbay Research Institute for Precision Medicine, Gulf Medical University, Ajman 4184, United Arab Emirates 2 Armstrong Oxygen Biology Research Center and Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA 3 INSERM UMR 1356, Next-Generation Immuno-Oncology Research and Therapy in Pediatric and Adult Cancer, Gustave Roussy, Faculty of Medicine, University Paris-Saclay, 94805 Villejuif, France 4 Gastrointestinal Research Unit, Department of General Surgery and Surgical Oncology, Cantonal Hospital Aarau, Tellstrasse 25, CH-5001 Aarau, Switzerland 5 Swiss Hepato-Pancreato-Biliary (HPB) and Transplantation Center, University Hospital Zurich, Raemistrasse 100, CH-8091 Zurich, Switzerland 6 Department of Surgery & Transplantation, University Hospital Zurich, Raemistrasse 100, CH-8091 Zurich, Switzerland 7 Tumor Immunotherapy and Microenvironment (TIME) Group, Department of Cancer Research, Luxembourg Institute of Health, 6A, Rue Nicolas-Ernest Barblé, L-1210 Luxembourg City, Luxembourg * Correspondence: [salem.chouaib@gustaveroussy.fr](salem.chouaib@gustaveroussy.fr); Tel.: +971-6-7431333 Abstract Pancreatic ductal adenocarcinoma (PDAC) remains among the deadliest cancers, with a 5-year survival rate of 13% and broad resistance to therapy. It is driven by severe tumor hypoxia from desmoplasia, aberrant vasculature, and high interstitial pressure. Hypoxia stabilizes hypoxia-inducible factors (HIFs), reshaping the tumor microenvironment (TME) into a nutrient-poor, acidic milieu that fosters immune exclusion and suppression. While immune checkpoint inhibitors (ICIs) have revolutionized treatment, PDAC responses have been negligible. As hypoxia centrally drives PDAC’s ICI-refractory TME, targeted alleviation could offer synergy with ICIs; however, no such combination is being applied in the clinic. One impediment could be the one-size-fits-all approach when investigating hypoxia-modifying therapy. Indeed, using hypoxia gene signatures, we and others have shown that PDAC tumors are not equally hypoxic, with patients having more hypoxic tumors experiencing worse survival and immunosuppressed TME. This review dissects hypoxia’s mechanistic role in PDAC immune evasion and gives an update on the therapeutic advances that directly or indirectly target hypoxia, such as the inhibition of HIFs, hypoxia-activated prodrugs, and vascular and oxygen delivery approaches, with emphasis on their potential to enhance responses to ICIs. It further evaluates the need for hypoxia biomarkers and proposes gene signatures as detection tools to enable precision hypoxia modulation, potentially converting immune-cold PDAC into an ICI-responsive disease. Keywords: hypoxia; immunotherapy; immunosuppression; hypoxia alleviation; hypoxia targeting; hypoxia gene signatures; pancreatic cancer 1. Introduction Pancreatic ductal adenocarcinoma (PDAC) is among the most lethal malignancies, with a five-year survival rate of 13% and broad resistance to cytotoxic and targeted therapies [1,2] . A defining hallmark of PDAC is tumor hypoxia, with tissue oxygen

FAQs

Why does tumor hypoxia play a central role in PDAC immune evasion?

Tumor hypoxia stabilizes hypoxia-inducible factors (HIFs), reprogramming the tumor microenvironment into a nutrient-poor, acidic milieu that fosters immune exclusion and suppression.

How does hypoxia affect responses to immune checkpoint inhibitors in pancreatic cancer?

Although immune checkpoint inhibitors have transformed some cancers, PDAC responses have been negligible because hypoxia-driven tumor microenvironment remodeling supports immune suppression and resistance.

What therapeutic strategies are discussed for targeting hypoxia in PDAC?

The review highlights approaches including inhibition of HIFs, hypoxia-activated prodrugs, and vascular or oxygen delivery strategies, aiming to enhance sensitivity to immune checkpoint inhibitors.

Sep 22, 2026

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