# Neutrophils in the hepatocellular carcinoma microenvironment: orchestrators of progression and immunity

**Authors:** Yanjie Lian, Li Wang, Jiuchong Wang, Dan Zhu, Wenliang Lyu

PMC · DOI: 10.3389/fimmu.2026.1735189 · 2026-02-03

## TL;DR

This paper explores how neutrophils influence liver cancer progression and immunity, aiming to improve treatment strategies.

## Contribution

The paper highlights neutrophils as key regulators in the HCC tumor microenvironment and proposes new therapeutic strategies.

## Key findings

- Neutrophils play dual roles in promoting and inhibiting HCC progression.
- Neutrophil interactions with other TME cells are critical for tumor dynamics.
- Targeting neutrophil pathways offers potential for new HCC therapies.

## Abstract

Among all malignant tumors, liver cancer is highly common, and hepatocellular carcinoma (HCC) stands as its most frequently seen pathological form. The majority of HCC patients are difficult to be detected or treated at an early stage. Concurrently, the postoperative recurrence rate remains relatively high, leading to a poor clinical prognosis of HCC. Recently, immunotherapy has made it promising to treat HCC. tumor microenvironment (TME) matters considerably in HCCprogression and metastasis. Neutrophils belong to the innate immune system’s essential elements, and their role as key regulators in the HCC-TME is becoming more widely recognized. By studying neutrophils ‘ pro-tumor and anti-tumor mechanisms in HCC, it is expected to gain a deeper comprehension of the functions of neutrophils and further reveal their biological characteristics. In addition, we analyze the crosstalk between neutrophils and other cellular constituents of the TME, and discuss emerging therapeutic strategies that target neutrophil-centric pathways. A deeper understanding of neutrophil biology will both illuminate the complexity of immune networks in liver cancer and offer a theoretical framework for HCC prevention and treatment.

## Linked entities

- **Diseases:** hepatocellular carcinoma (MONDO:0007256), liver cancer (MONDO:0002691)

## Full-text entities

- **Genes:** Mmp9 (matrix metallopeptidase 9) [NCBI Gene 17395] {aka B/MMP9, Clg4b, Gel B, MMP-9, pro-MMP-9}, Myd88 (myeloid differentiation primary response gene 88) [NCBI Gene 17874], SPINK5 (serine peptidase inhibitor Kazal type 5) [NCBI Gene 11005] {aka LEKTI, LETKI, NETS, NS, VAKTI}, TP53 (tumor protein p53) [NCBI Gene 7157] {aka BCC7, BMFS5, LFS1, P53, TRP53}, FLT3 (fms related receptor tyrosine kinase 3) [NCBI Gene 2322] {aka CD135, FLK-2, FLK2, STK1}, CCL3 (C-C motif chemokine ligand 3) [NCBI Gene 6348] {aka G0S19-1, LD78, LD78ALPHA, MIP-1-alpha, MIP1A, SCI}, PADI4 (peptidyl arginine deiminase 4) [NCBI Gene 23569] {aka PAD, PAD4, PADI5, PDI4, PDI5}, Cxcr2 (C-X-C motif chemokine receptor 2) [NCBI Gene 12765] {aka CD128, CDw128, Cmkar2, Gpcr16, IL-8Rh, IL-8rb}, IL33 (interleukin 33) [NCBI Gene 90865] {aka C9orf26, DVS27, IL1F11, NF-HEV, NFEHEV}, NOS2 (nitric oxide synthase 2) [NCBI Gene 4843] {aka HEP-NOS, INOS, NOS, NOS2A}, IRF9 (interferon regulatory factor 9) [NCBI Gene 10379] {aka IRF-9, ISGF3, ISGF3G, p48}, STAT1 (signal transducer and activator of transcription 1) [NCBI Gene 6772] {aka CANDF7, IMD31A, IMD31B, IMD31C, ISGF-3, STAT91}, S100A9 (S100 calcium binding protein A9) [NCBI Gene 6280] {aka 60B8AG, CAGB, CFAG, CGLB, L1AG, LIAG}, VEGFA (vascular endothelial growth factor A) [NCBI Gene 7422] {aka L-VEGF, MVCD1, VEGF, VPF}, HGF (hepatocyte growth factor) [NCBI Gene 3082] {aka DFNB39, F-TCF, HGFB, HPTA, SF}, IL12B (interleukin 12B) [NCBI Gene 3593] {aka CLMF, CLMF2, IL-12B, IMD28, IMD29, NKSF}, OLR1 (oxidized low density lipoprotein receptor 1) [NCBI Gene 4973] {aka CLEC8A, LOX1, LOXIN, SCARE1, SLOX1}, ARG1 (arginase 1) [NCBI Gene 383], CXCL8 (C-X-C motif chemokine ligand 8) [NCBI Gene 3576] {aka GCP-1, GCP1, IL8, LECT, LUCT, LYNAP}, NFKB1 (nuclear factor kappa B subunit 1) [NCBI Gene 4790] {aka CVID12, EBP-1, KBF1, NF-kB, NF-kB1, NF-kappa-B1}, IL15 (interleukin 15) [NCBI Gene 3600] {aka IL-15}, ICAM1 (intercellular adhesion molecule 1) [NCBI Gene 3383] {aka BB2, CD54, P3.58}, TLR9 (toll like receptor 9) [NCBI Gene 54106] {aka CD289}, CXADRP1 (CXADR pseudogene 1) [NCBI Gene 653108] {aka CAR, CXADRP}, TLR3 (toll like receptor 3) [NCBI Gene 7098] {aka CD283, IIAE2, IMD83}, Ifng (interferon gamma) [NCBI Gene 15978] {aka IFN-g, If2f, Ifg}, CXCR2 (C-X-C motif chemokine receptor 2) [NCBI Gene 3579] {aka CD182, CDw128b, CMKAR2, IL8R2, IL8RA, IL8RB}, COX2 (cytochrome c oxidase subunit II) [NCBI Gene 4513] {aka COII, MTCO2}, Tlr4 (toll-like receptor 4) [NCBI Gene 21898] {aka Lps, Ly87, Ran/M1, Rasl2-8}, OSM (oncostatin M) [NCBI Gene 5008], PKM (pyruvate kinase M1/2) [NCBI Gene 5315] {aka CTHBP, HEL-S-30, OIP3, PK3, PKM2, TCB}, Nfkb1 (nuclear factor of kappa light polypeptide gene enhancer in B cells 1, p105) [NCBI Gene 18033] {aka NF-KB1, NF-kappaB, NF-kappaB1, p105, p50, p50/p105}, PTGS2 (prostaglandin-endoperoxide synthase 2) [NCBI Gene 5743] {aka COX-2, COX2, GRIPGHS, PGG/HS, PGHS-2, PHS-2}, TLR4 (toll like receptor 4) [NCBI Gene 7099] {aka ARMD10, CD284, TLR-4, TOLL}, KDR (kinase insert domain receptor) [NCBI Gene 3791] {aka CD309, FLK1, VEGFR, VEGFR2}, STAT3 (signal transducer and activator of transcription 3) [NCBI Gene 6774] {aka ADMIO, ADMIO1, APRF, HIES}, Ccl4 (C-C motif chemokine ligand 4) [NCBI Gene 20303] {aka AT744.1, Act-2, MIP-1B, Mip1b, Scya4}, TNF (tumor necrosis factor) [NCBI Gene 7124] {aka DIF, IMD127, TNF-alpha, TNFA, TNFSF2, TNLG1F}, MMP8 (matrix metallopeptidase 8) [NCBI Gene 4317] {aka CLG1, HNC, MMP-8, PMNL-CL}, CSF3 (colony stimulating factor 3) [NCBI Gene 1440] {aka C17orf33, CSF3OS, GCSF}, Ccr5 (C-C motif chemokine receptor 5) [NCBI Gene 12774] {aka AM4-7, CD195, Cmkbr5}, CXCL1 (C-X-C motif chemokine ligand 1) [NCBI Gene 2919] {aka FSP, GRO1, GROa, MGSA, MGSA-a, NAP-3}, Ccl2 (C-C motif chemokine ligand 2) [NCBI Gene 20296] {aka HC11, JE, MCAF, MCP-1, MCP1, SMC-CF}, LDHA (lactate dehydrogenase A) [NCBI Gene 3939] {aka GSD11, HEL-S-133P, LDHM, PIG19}, NCR1 (natural cytotoxicity triggering receptor 1) [NCBI Gene 9437] {aka CD335, LY94, NK-p46, NKP46}, IFNB1 (interferon beta 1) [NCBI Gene 3456] {aka IFB, IFF, IFN-beta, IFNB}, CTSG (cathepsin G) [NCBI Gene 1511] {aka CATG, CG}, GPC3 (glypican 3) [NCBI Gene 2719] {aka DGSX, GTR2-2, MXR7, OCI-5, SDYS, SGB}, SIRPA (signal regulatory protein alpha) [NCBI Gene 140885] {aka BIT, CD172A, MFR, MYD-1, MYD1, P84}, BHLHE40 (basic helix-loop-helix family member e40) [NCBI Gene 8553] {aka BHLHB2, Clast5, DEC1, HLHB2, SHARP-2, SHARP2}, CXCL2 (C-X-C motif chemokine ligand 2) [NCBI Gene 2920] {aka CINC-2a, GRO2, GROb, MGSA-b, MIP-2a, MIP2}, COXFA4L2 (cytochrome c oxidase hypoxia associated subunit FA4L2) [NCBI Gene 56901] {aka MISTRH, NDUFA4L2, NUOMS}, CXCL12 (C-X-C motif chemokine ligand 12) [NCBI Gene 6387] {aka IRH, PBSF, SCYB12, SDF1, TLSF, TPAR1}, GAPDH (glyceraldehyde-3-phosphate dehydrogenase) [NCBI Gene 2597] {aka G3PD, GAPD, HEL-S-162eP}, CCDC25 (coiled-coil domain containing 25) [NCBI Gene 55246], SELE (selectin E) [NCBI Gene 6401] {aka CD62E, ELAM, ELAM1, ESEL, LECAM2, selectin-e}, HMOX1 (heme oxygenase 1) [NCBI Gene 3162] {aka HMOX1D, HO-1, HSP32, bK286B10}, EGFR (epidermal growth factor receptor) [NCBI Gene 1956] {aka ERBB, ERBB1, ERRP, HER1, NISBD2, NNCIS}, MMP12 (matrix metallopeptidase 12) [NCBI Gene 4321] {aka HME, ME, MME, MMP-12}, CD4 (CD4 molecule) [NCBI Gene 920] {aka CD4mut, IMD79, Leu-3, OKT4D, T4}
- **Diseases:** hypoxia (MESH:D000860), gastric cancer (MESH:D013274), hypoxic (MESH:D002534), alcoholic metabolism-associated steatohepatitis (MESH:D005235), MASH (MESH:D005234), intrahepatic cholangiocarcinoma (MESH:D018281), carcinogenesis (MESH:D063646), endothelial dysfunction (MESH:D014652), Cancer (MESH:D009369), NASH-HCC (MESH:D065626), Hepatic fibrosis (MESH:D008103), cystic fibrosis (MESH:D003550), cirrhosis (MESH:D005355), glioma (MESH:D005910), melanoma (MESH:D008545), pancreatic ductal adenocarcinoma (MESH:D021441), chronic liver diseases (MESH:D008107), chronic inflammation (MESH:D007249), TAMs (MESH:D000072716), HCC (MESH:D006528), liver tumor (MESH:D008113), ALD (MESH:D008108), bacterial infections (MESH:D001424), liver dysfunction (MESH:D017093), Child-Pugh B/C (MESH:D019694), cytotoxicity (MESH:D064420), HCC metastasis (MESH:D009362), thrombosis (MESH:D013927), viral hepatitis (MESH:D014777), tumorigenic (MESH:D002471), death (MESH:D003643)
- **Chemicals:** navarixin (MESH:C516686), SX-682 (MESH:C000712522), aspirin (MESH:D001241), Galunisertib (MESH:C557799), atezolizumab (MESH:C000594389), cabozantinib (MESH:C558660), PGE2 (MESH:D015232), lactate (MESH:D019344), peroxide lipids (MESH:D008054), pyruvate (MESH:D019289), GNE-140 (MESH:C000618756), AZD5069 (MESH:C000597960), Nivolumab (MESH:D000077594), ROS (MESH:D017382), R848 (MESH:C402365), ATP (MESH:D000255), durvalumab (MESH:C000613593), Lenvatinib (MESH:C531958), pembrolizumab (MESH:C582435), arginine (MESH:D001120), NO (MESH:D009614), FX11 (-), hydroxychloroquine (MESH:D006886)
- **Species:** Mus musculus (house mouse, species) [taxon 10090], Homo sapiens (human, species) [taxon 9606]

## Figures

1 figure with captions in the complete paper: https://tomesphere.com/paper/PMC12909486/full.md

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Source: https://tomesphere.com/paper/PMC12909486