Multiomic sequencing identifies myeloid cell associations with neoadjuvant chemotherapy treatment response in pancreatic adenocarcinoma (PDAC)

Pancreatic ductal adenocarcinoma (PDAC) is among the deadliest human malignancies with poor prognosis and limited therapeutic success. Despite significant advancements in therapeutic strategies over recent decades, the development of effective treatments for pancreatic ductal adenocarcinoma (PDAC) remains a major challenge due to its complex tumor microenvironment (TME). The PDAC TME is characterized by tumor-infiltrating immune cells, immunosuppressive cells, and cancer-associated fibroblasts (CAFs). The immune components, particularly the myeloid cells, play a role in the tumor microenvironment (TME). The myeloid compartment of the TME comprises a functionally diverse compartment of the TME, capable of exerting both pro-tumorigenic and antitumor effects depending on their phenotypic state and microenvironmental cues. In this study, we leveraged single-nucleus multiomic sequencing (snRNA-seq and snATAC-seq) of human pancreatic ductal adenocarcinoma (PDAC) tumors to dissect the immune landscape, particularly the myeloid subsets, in patients who received neoadjuvant chemotherapy, stratified as responders or non-responders based on histopathological evaluation. Our integrative analysis revealed striking differences in myeloid cell composition and transcriptional states, with a notable enrichment of lipid-associated macrophages (LAMs) in chemotherapy responders. LAMs exhibited a transcriptional program enriched for lipid metabolism, phagocytosis, and inflammatory signaling. Pseudotime and chromatin accessibility analyses from the ATAC-Seq data positioned LAMs as terminally differentiated, metabolically reprogrammed macrophages, shaped by immune and environmental cues. ChromVAR analysis identified AP-1, C/EBP, and metabolic transcription factor motif enrichment in LAMs from responders, indicating active immunometabolic states associated with treatment efficacy. These findings implicate LAMs as potential biomarkers and effectors of chemotherapeutic response in PDAC, providing new insights into myeloid cell plasticity and therapeutic reprogramming in the TME.