Overcoming multidimensional immunotherapy resistance in PDAC: from microenvironment to clinic

Area of Science:

• Oncology
• Immunology
• Cancer Research

Background:

• Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal cancer with poor immunotherapy response rates (<10% ORR).
• The immunosuppressive tumor microenvironment (TME) in PDAC, characterized by stromal desmoplasia, myeloid dominance, T-cell exclusion, and impaired antigen presentation, creates an immune-privileged niche.
• Key resistance pathways (e.g., cGAS-STING, Hedgehog, NF-κB) contribute to immunotherapy failure.

Purpose of the Study:

• To review preclinical and clinical evidence (2018-2026) dissecting PDAC's immunosuppressive TME and resistance mechanisms.
• To discuss emerging immunotherapy strategies for PDAC.
• To propose a novel framework for designing more effective, multidimensional immunotherapies for PDAC.

Main Methods:

• Comprehensive review of preclinical and clinical literature from 2018-2026.
• Analysis of key PDAC TME components and immune resistance pathways.
• Integration of emerging therapeutic strategies and conceptual frameworks.

Main Results:

• Stromal desmoplasia, myeloid dominance, T-cell exclusion, and impaired antigen presentation create a resistant TME.
• Emerging strategies include CAR-T cells, mRNA neoantigen vaccines, STING agonists, CD39/CD73 blockade, and cDC1-based vaccines.
• Current single-target interventions show limited durable responses.

Conclusions:

• A multidimensional, biomarker-driven approach is necessary for effective PDAC immunotherapy.
• The proposed "3D+R" framework (De-desmoplasia, De-adenosine, De-novo antigen, Rational sequencing) offers a roadmap for optimizing treatment.
• Reshaping PDAC's immune-desert phenotype towards an immune-reactive state through integrated strategies may lead to durable and predictable clinical benefit.