Immunosuppressive tumor microenvironment shape pancreatic cancer unresponsive to current immunotherapies

Abstract

Pancreatic ductal adenocarcinoma remains largely refractory to current immunotherapies due to a profoundly immunosuppressive tumor microenvironment dominated by regulatory T cells (Tregs), myeloid-derived suppressor cells (MDSCs), and tumor-associated macrophages (TAMs). These cells form a coordinated network that suppresses cytotoxic T lymphocytes and fosters tumor progression. Key mechanisms include Tregs secreting inhibitory cytokines like transforming growth factor β and interleukin-10, and upregulating immune checkpoints such as cytotoxic T-lymphocyte-associated protein 4 and programmed death 1. MDSCs deplete essential nutrients like arginine and generate reactive oxygen species, while TAMs polarized to an M2 phenotype produce chemokines including C-C motif chemokine ligand 2 and C-X-C motif chemokine ligand 12, which recruit more suppressive cells. Single-cell transcriptomic studies have uncovered prognostically relevant cellular subsets, such as caspase-4-high Tregs, highlighting this heterogeneity. Reciprocal signaling via interleukin-10 and transforming growth factor β creates a self-reinforcing immunosuppressive loop. Emerging therapeutic strategies aim to disrupt this axis by depleting Tregs (e.g., anti-CD25), blocking MDSC recruitment (e.g., CCR2 inhibitors), or reprogramming TAMs (e.g., CD40 agonists), often in combination with programmed death 1/programmed death-ligand 1 blockade. An integrated approach targeting these populations holds promise for converting pancreatic ductal adenocarcinoma into an immunologically responsive tumor.

Keywords: Pancreatic ductal adenocarcinoma; Immunosuppressive tumor microenvironment; Regulatory T cells; Myeloid-derived suppressor cells; Tumor-associated macrophages

Core Tip: Pancreatic ductal adenocarcinoma is characterized by a highly immunosuppressive tumor microenvironment dominated by regulatory T cells, myeloid-derived suppressor cells, and tumor-associated macrophages. These cells form a synergistic network that promotes immune evasion and resistance to immunotherapy. Recent advances in single-cell transcriptomics have revealed cellular heterogeneity and identified novel therapeutic targets. Emerging strategies focus on depleting or reprogramming these immunosuppressive populations, often in combination with checkpoint blockade or chemotherapy. A multi-target approach is essential to convert pancreatic ductal adenocarcinoma from an immunologically “cold” to “hot” tumor and improve patient outcomes.