Table 2.

Updating subtypes based on PDAC stroma.

Study	Multi-omics involved	Main discovery	Subtypes/classifier
2017 Knudsen75 (n = 109 PDAC cases)	Immunohistochemical analysis and staining and exome sequencing	Different stromal phenotypes: various prognostic impacts; distinct glycolysis-related and hypoxic markers; differentiated immune infiltrations	Four major subtypes: cold, mutationally cold, hot, and mutationally active
2019 Neuzillet78 (n = 96 PDAC samples)	RNA-Seq	Various CAF classifications could co-exist in a patient. Each CAF subtype has its specific phenotypes including immune-related pathways, proliferative rates, and gene expression profiles, and displays different survival outcomes	Four distinct CAF subtypes
2021 Barbara77 (n = 32 treatment-naive PDAC resections)	Shotgun proteomics and RNA-Seq	Two kinds of reactive and deserted sub-TMEs exhibit corresponding immune phenotypes and CAF differentiation states. Intra-tumoral sub-TME co-occurrence performs tumor-promoting and chemoprotective functions separately, linking stromal heterogeneity to patient outcome	A prognostic classifier of “TME PHENOtyper"
2021 Tu79 (n = 23 PDX and FACS-isolated tumor tissue biopsies)	ATAC-Seq, ChIP-Seq and RNA-Seq	Basal-like: regulated by cJUN/AP1; TNF-α-secreting macrophages recruited; pharmacological value of BRD4. Classical: regulated by JUNB/AP1	TNF-α+ macrophages regulate phenotypic properties
2022 Wang76 (n = 269 PDAC samples)	PDAC expression profile data and ssGSEA algorithm	Multiple immune expression patterns, and immune and stromal enrichment molecular markers were discovered	Four subtypes based on different combinations of immune and stromal status
2023 Zheng81 (n = 11 publicly available datasets from GEO, TCGA, and ICGC)	scRNA-seq and bulk RNA-seq	High-TMGS: more frequent germline mutations and TMB; attenuated immune infiltration but enhanced ICB response rate. Low-TMGS: responsible for chemotherapy and targeted therapy	A constructed TMGS system based on 10 T cell marker genes to predict survival status and treatment response
2023 Wang80 (n = 5 PMN coupled with tumor-infiltrating immune cells)	Single-cell transcriptomics	TAN-1: poor prognosis. TAN-4: enriched in interferon-stimulated genes	Four distinct TAN subtypes

Abbreviations: ATAC-seq, assay for transposase accessible chromatin with high-throughput sequencing; ChIP-Seq, chromatin immunoprecipitation sequencing; CAF, cancer-associated fibroblast; PMN, peripheral polymorphonuclear leukocytes; TANs, tumor-associated neutrophils; ICB, immune checkpoint blockade therapy.