Neoadjuvant Therapy-Induced Remodeling in Pancreatic Ductal Adenocarcinoma: Multimodal Spatial Analysis and Prognosis

Xiaofei Zhang; Ruoxin Lan; Danting Li; Yongjun Liu; Sonu Kalyan; Momin Iqbal; Nancy Liu; Jerry Zhang; Iman Hanna; Mala Gupta; Chaohui L Zhao; Weiguo Liu; Jonathan Melamed; Michael Shusterman; Jessica Widmer; John Allendorf; Yao-Zhong Liu

doi:10.1111/cas.70320

Neoadjuvant Therapy-Induced Remodeling in Pancreatic Ductal Adenocarcinoma: Multimodal Spatial Analysis and Prognosis

Cancer Sci. 2026 Jan 13. doi: 10.1111/cas.70320. Online ahead of print.

Authors

Xiaofei Zhang¹, Ruoxin Lan², Danting Li², Yongjun Liu³, Sonu Kalyan¹, Momin Iqbal¹, Nancy Liu⁴, Jerry Zhang⁵, Iman Hanna¹, Mala Gupta¹, Chaohui L Zhao¹, Weiguo Liu¹, Jonathan Melamed¹, Michael Shusterman⁶, Jessica Widmer⁷, John Allendorf⁸, Yao-Zhong Liu²

Affiliations

¹ Department of Pathology, New York University Grossman Long Island School of Medicine, Long Island, New York, USA.
² Department of Biostatistics and Data Science, Tulane University School of Public Health and Tropical Medicine, New Orleans, Louisiana, USA.
³ Department of Laboratory Medicine and Pathology, University of Washington School of Medicine, Seattle, Washington, USA.
⁴ Department of Chemistry, University of Washington School of Medicine, Seattle, Washington, USA.
⁵ Skyline High School, Sammamish, Washington, USA.
⁶ Department of Oncology, New York University Grossman Long Island School of Medicine, Long Island, New York, USA.
⁷ Department of Gastroenterology, New York University Grossman Long Island School of Medicine, Long Island, New York, USA.
⁸ Department of Surgery, New York University Grossman Long Island School of Medicine, Long Island, New York, USA.

PMID: 41531168
DOI: 10.1111/cas.70320

Abstract

Neoadjuvant therapy (NAT) is increasingly used for pancreatic ductal adenocarcinoma (PDAC); yet most patients only achieve partial response. Pathological treatment response grading focuses on assessing residual tumor burden, often overlooking changes in tumor microenvironment (TME). To address this gap, we compared tumor cells and TME of 13 NAT-naïve and 23 post-NAT PDACs using integrated spatial pathomics and transcriptomics, with validation in an independent single-cell spatial dataset. NAT significantly reduced tumor burden (14.7%-6.2%, p = 0.004), but systemic comparison of 13 cytomorphometric features of tumor cells alone did not reliably distinguish between naïve and NAT cases. In contrast, NAT profoundly remodeled TME by increasing cancer-associated fibroblast (CAF) and CD8⁺ T cell densities, promoting CD8⁺ T cell-tumor cell proximity and fibrosis, reducing tumor-associated neutrophils, and redistributing tertiary lymphoid structures (TLSs). Spatial transcriptomics shows NAT induced apoptosis, DNA-damage response, and AGC-kinase (S_TK_X) signaling in tumor cells, and upregulated complement pathway, p53 signaling, and cellular senescence program in TME. Cross-platform single-cell spatial analysis revealed decreased regulatory T cells (Treg) and a shift from myofibroblastic (mCAF) to inflammatory CAF (iCAF). Importantly, post-NAT patients with more fibrosis had longer overall survival (p = 0.02), and higher B-cell density showed a favorable trend (p = 0.06). Together, these results suggest that beyond tumor debulking, NAT induces a coordinated TME remodeling characterized by fibroblast reprogramming, matrix fibrosis, and immune spatial reorganization. Incorporating assessment of NAT-induced stromal and immune changes into TRG may improve prognostication and guide more precise therapy in post-NAT PDAC.

Keywords: neoadjuvant therapy (NAT); pancreatic ductal adenocarcinoma (PDAC); spatial analysis; spatial transcriptomics; tumor microenvironment (TME).

Abstract

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