Hypoxic Tumor Microenvironment Targeting: Opportunities and Challenges for Pancreatic Cancer Immunotherapy.

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.