Hypoxia-related bioinformatic signatures associated with prognosis and tumor microenvironment of pancreatic cancer: Current status, concerns, and future perspectives

Table 2 The role of hypoxic-related prognostic models in the tumor microenvironment and antitumor therapy and their experimental validation and underlying mechanisms

Ref.	TME changes in a high-risk group	Therapeutic significance	Experimental validation	Mechanism
Yang et al[9]	CD8+ T cells, T cells, B cells, plasmacytoid dendritic cells, immature dendritic cells, and cytotoxic cells	Higher sensitivity to cisplatin and paclitaxel in the high-risk group	qPCR: MRNA expression	None
Ren et al[10]	CD8+ T cells, CD4+ T cells, and endothelial cells; Macrophages and fibroblasts	Higher sensitivity to paclitaxel, erlotinib, and cisplatin in the high-risk group; No significant difference in TMB, PD1, PD-L1, CTLA4 and IPS score	None	None
Huang et al[11]	None	KRAS mutations are more frequent in the hypoxic subtype	qPCR: MRNA expression	None
Li et al[12]	T cell exclusion scores	Lower PD1 expression in the high-risk subgroup	None	None
Ren et al[13]	CD8+ T cells, B cells, macrophage, eosinophil, and monocyte; Immune activation score	Higher sensitivity to paclitaxel and erlotinib in the high-risk group; No significant difference in TMB, MSI, and IPS score	None	None
Zhou et al[14]	CD8+ T cells, activated CD4+ memory T cells, naïve B cells, and plasma cells; M0 macrophages; Scores in CD4+ T cell recruiting, Th17 cell recruiting, dendritic cell recruiting, macrophage recruiting, and killing of cancer cells	None	qPCR: MRNA expression; Wound-healing assay: Migration; Transwell assay: Invasion	ChIP assay: BHLHE40/TLR3 axis
Sun et al[15]	CD8+ T cells and B cells	None	qPCR: MRNA expression; MTT assay: Proliferation; Transwell assay: Invasion	ChIP assay and luciferase reporter assay: HIF-1α/ TSPOAP1-AS1 axis
Tian et al[16]	CD8+ T cells and regulatory T cell	Lower PD1 and CTLA4 expression in a high-risk group	qPCR: MRNA expression	None
Zhang et al[17]	T cells; M0 macrophages	Higher LDHA methylation in pancreatic cancer tissues	None	None
Chen et al[18]	CD8+ T cells, follicular helper T cells, memory B cells, monocytes, M1 macrophages, M2 macrophages, resting mast cells, and eosinophils; Immune score and stromal score	Higher TMB in the high-risk groups	None	None
Ding et al[19]	CD8+ T cells, plasma cells, and naïve B cells; M2 macrophages, resting memory CD4+ T cells, and resting natural killer cells	None	None	None

BHLHE40: Basic helix-loop-helix family member e40; ChIP: Chromatin immunoprecipitation; CTLA4: Cytotoxic T-lymphocyte-associated protein 4; HIF-1α: Hypoxia-inducible factor 1α; IPS: Immunophenoscore; KRAS: Kirsten rat sarcoma viral oncogene homologue; LDHA: Lactate dehydrogenase A; MSI: Microsatellite instability; MTT: 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide; PD1: Programmed cell death protein 1; PD-L1: Programmed death ligand 1; qPCR: Quantitative real-time PCR; TMB: Tumor mutation burden; TSPOAP1-AS1: TSPO-associated protein 1 antisense RNA 1; TLR3: Toll-like receptor 3.