# Single-cell dissection of hepatocellular carcinoma immunity: from heterogeneous subtypes to precision therapeutics

**Authors:** Yuni Liang, Hemeng Wu, Yunshan Qiu, Qiulian Mo, Peipei Chen, Mingfen Li, Hongsheng Lin

PMC · DOI: 10.3389/fimmu.2026.1744845 · Frontiers in Immunology · 2026-02-11

## TL;DR

This paper reviews how single-cell sequencing helps understand the immune environment in liver cancer, aiming to improve precision treatments.

## Contribution

The paper provides a comprehensive synthesis of immune cell classifications in HCC using single-cell data and their therapeutic implications.

## Key findings

- Single-cell sequencing reveals detailed immune cell heterogeneity in hepatocellular carcinoma.
- Immune subsets in HCC are classified based on their functional states and biomarker gene profiles.
- Understanding immune cell dynamics in the tumor microenvironment can guide precision therapeutic strategies.

## Abstract

Hepatocellular carcinoma (HCC) represents one of the most prevalent malignancies worldwide and poses a critical public health challenge due to difficulties in early diagnosis, therapy resistance, and high mortality rates. The complex tumor microenvironment (TME) of HCC plays a pivotal role in tumor progression, immune evasion, metastasis, and treatment resistance. Single-cell sequencing (scRNA-seq) has emerged as a revolutionary tool for resolving the intricacies and cellular heterogeneity of the TME, with its applications in advancing therapeutic research attracting considerable attention. As the primary battleground for antitumor immune responses, the HCC tumor TME warrants comprehensive analysis of immune cell subsets at distinct developmental and functional states to elucidate the complexity of tumor immunology. This review synthesizes extensive research on TME immune cellular subpopulations, in order to summarize mainstream classifications of immune subsets at single-cell resolution and analyze their functional significance and therapeutic value through biomarker gene profiling.

## Linked entities

- **Diseases:** hepatocellular carcinoma (MONDO:0007256), HCC (MONDO:0007256)

## Full-text entities

- **Genes:** EPHB2 (EPH receptor B2) [NCBI Gene 2048] {aka BDPLT22, CAPB, DRT, EK5, EPHT3, ERK}, SPP1 (secreted phosphoprotein 1) [NCBI Gene 6696] {aka BNSP, BSPI, ETA-1, OPN}, CXCR3 (C-X-C motif chemokine receptor 3) [NCBI Gene 2833] {aka CD182, CD183, CKR-L2, CMKAR3, GPR9, IP10-R}, ISG15 (ISG15 ubiquitin like modifier) [NCBI Gene 9636] {aka G1P2, IFI15, IMD38, IP17, UCRP, hUCRP}, LEF1 (lymphoid enhancer binding factor 1) [NCBI Gene 51176] {aka ECTD1, ECTD17, LEF-1, TCF10, TCF1ALPHA, TCF7L3}, CXCL13 (C-X-C motif chemokine ligand 13) [NCBI Gene 10563] {aka ANGIE, ANGIE2, BCA-1, BCA1, BLC, BLR1L}, NCAM1 (neural cell adhesion molecule 1) [NCBI Gene 4684] {aka CD56, MSK39, NCAM}, CD38 (CD38 molecule) [NCBI Gene 952] {aka ADPRC 1, ADPRC1, cADPR1}, HLA-C (major histocompatibility complex, class I, C) [NCBI Gene 3107] {aka D6S204, HLA-JY3, HLAC, HLC-C, MHC, PSORS1}, IL10 (interleukin 10) [NCBI Gene 3586] {aka CSIF, GVHDS, IL-10, IL10A, TGIF}, TNF (tumor necrosis factor) [NCBI Gene 7124] {aka DIF, IMD127, TNF-alpha, TNFA, TNFSF2, TNLG1F}, TCF7 (transcription factor 7) [NCBI Gene 6932] {aka TCF-1}, KLRC2 (killer cell lectin like receptor C2) [NCBI Gene 3822] {aka CD159c, NKG2-C, NKG2C}, IL22 (interleukin 22) [NCBI Gene 50616] {aka IL-21, IL-22, IL-D110, IL-TIF, ILTIF, TIFIL-23}, MMP9 (matrix metallopeptidase 9) [NCBI Gene 654325], CCL19 (C-C motif chemokine ligand 19) [NCBI Gene 6363] {aka CKb11, ELC, MIP-3b, MIP3B, SCYA19}, CCR7 (C-C motif chemokine receptor 7) [NCBI Gene 1236] {aka BLR2, CC-CKR-7, CCR-7, CD197, CDw197, CMKBR7}, TRBV20OR9-2 (T cell receptor beta variable 20/OR9-2 (non-functional)) [NCBI Gene 6962] {aka CDR3, TCRBV20S2, TCRBV2O, TCRBV2S2O}, HLA-E (major histocompatibility complex, class I, E) [NCBI Gene 3133] {aka HLA-6.2, QA1}, CCL5 (C-C motif chemokine ligand 5) [NCBI Gene 6352] {aka D17S136E, RANTES, SCYA5, SIS-delta, SISd, TCP228}, HGF (hepatocyte growth factor) [NCBI Gene 3082] {aka DFNB39, F-TCF, HGFB, HPTA, SF}, CXCL9 (C-X-C motif chemokine ligand 9) [NCBI Gene 4283] {aka CMK, Humig, MIG, SCYB9, crg-10}, LAYN (layilin) [NCBI Gene 143903], CCL3 (C-C motif chemokine ligand 3) [NCBI Gene 6348] {aka G0S19-1, LD78, LD78ALPHA, MIP-1-alpha, MIP1A, SCI}, FAP (fibroblast activation protein alpha) [NCBI Gene 2191] {aka DPPIV, FAPA, FAPalpha, SIMP}, KLRC1 (killer cell lectin like receptor C1) [NCBI Gene 3821] {aka CD159A, NKG2, NKG2A}, IDO1 (indoleamine 2,3-dioxygenase 1) [NCBI Gene 3620] {aka IDO, IDO-1, INDO}, FOXP3 (forkhead box P3) [NCBI Gene 50943] {aka AIID, DIETER, IPEX, JM2, PIDX, XPID}, BCR (BCR activator of RhoGEF and GTPase) [NCBI Gene 613] {aka ALL, BCR1, CML, D22S11, D22S662, PHL}, ARG1 (arginase 1) [NCBI Gene 383], ERBB2 (erb-b2 receptor tyrosine kinase 2) [NCBI Gene 2064] {aka CD340, HER-2, HER-2/neu, HER2, MLN 19, MLN-19}, APOE (apolipoprotein E) [NCBI Gene 348] {aka AD2, APO-E, ApoE4, LDLCQ5, LPG}, SPP1 (secreted phosphoprotein 1) [NCBI Gene 397087] {aka Opn}, 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}, TXK (TXK tyrosine kinase) [NCBI Gene 7294] {aka BTKL, PSCTK5, PTK4, RLK, TKL}, ITGB1 (integrin subunit beta 1) [NCBI Gene 3688] {aka CD29, FNRB, GPIIA, MDF2, MSK12, VLA-BETA}, CLEC4C (C-type lectin domain family 4 member C) [NCBI Gene 170482] {aka BDCA-2, BDCA2, CD303, CLECSF11, CLECSF7, DLEC}, FCGR3A (Fc gamma receptor IIIa) [NCBI Gene 2214] {aka CD16-II, CD16A, FCG3, FCGR3, FCRIIIA, FcGRIIIA}, CD69 (CD69 molecule) [NCBI Gene 969] {aka AIM, BL-AC/P26, CLEC2C, EA1, GP32/28, MLR-3}, CD274 (CD274 molecule) [NCBI Gene 574058] {aka PDL1}, GZMK (granzyme K) [NCBI Gene 3003] {aka GrK, TRYP2}, TGFB1 (transforming growth factor beta 1) [NCBI Gene 7040] {aka CAEND1, CED, DPD1, IBDIMDE, LAP, TGF-beta1}, LAG3 (lymphocyte activating 3) [NCBI Gene 3902] {aka CD223}, CXCL11 (C-X-C motif chemokine ligand 11) [NCBI Gene 6373] {aka H174, I-TAC, IP-9, IP9, SCYB11, SCYB9B}, GZMA (granzyme A) [NCBI Gene 3001] {aka CTLA3, HFSP}, MRC1 (mannose receptor C-type 1) [NCBI Gene 4360] {aka CD206, CLEC13D, CLEC13DL, MMR, MRC1L1, bA541I19.1}, CD8A (CD8 subunit alpha) [NCBI Gene 925] {aka CD8, CD8alpha, IMD116, Leu2, p32}, CCR1 (C-C motif chemokine receptor 1) [NCBI Gene 1230] {aka CD191, CKR-1, CKR1, CMKBR1, HM145, MIP1aR}, IL23R (interleukin 23 receptor) [NCBI Gene 149233] {aka PSORS7}, CCR4 (C-C motif chemokine receptor 4) [NCBI Gene 1233] {aka CC-CKR-4, CD194, CKR4, CMKBR4, ChemR13, HGCN:14099}, AXL (AXL receptor tyrosine kinase) [NCBI Gene 558] {aka ARK, AXL3, JTK11, Tyro7, UFO}, BCL6 (BCL6 transcription repressor) [NCBI Gene 604] {aka BCL5, BCL6A, LAZ3, ZBTB27, ZNF51}, CTLA4 (cytotoxic T-lymphocyte associated protein 4) [NCBI Gene 1493] {aka ALPS5, CD, CD152, CELIAC3, CTLA-4, GRD4}, TCL1A (TCL1 family AKT coactivator A) [NCBI Gene 8115] {aka TCL1}, CXCL10 (C-X-C motif chemokine ligand 10) [NCBI Gene 3627] {aka C7, IFI10, INP10, IP-10, SCYB10, crg-2}, PRF1 (perforin 1) [NCBI Gene 5551] {aka HPLH2, P1, PFP}, IL6 (interleukin 6) [NCBI Gene 3569] {aka BSF-2, BSF2, CDF, HGF, HSF, IFN-beta-2}, CCR5 (C-C motif chemokine receptor 5) [NCBI Gene 1234] {aka CC-CKR-5, CCCKR5, CCR-5, CD195, CKR-5, CKR5}, CCL21 (C-C motif chemokine ligand 21) [NCBI Gene 6366] {aka 6Ckine, CKb9, ECL, SCYA21, SLC, TCA4}
- **Diseases:** esophageal squamous cell carcinoma (MESH:D000077277), hepatitis B and C infections (MESH:D006509), graft-versus-host disease (MESH:D006086), diabetes (MESH:D003920), Cancer (MESH:D009369), AD (MESH:D000544), neurotoxicity (MESH:D020258), multiple myeloma (MESH:D009101), CLL (MESH:D015451), cirrhotic (MESH:D000094724), melanoma (MESH:D008545), fibrosis (MESH:D005355), metabolic syndrome (MESH:D024821), HL (MESH:C538324), chronic inflammation (MESH:D007249), hypoxia (MESH:D000860), NK (MESH:D000077428), non-small cell lung cancer (MESH:D002289), systemic lupus erythematosus (MESH:D008180), hematologic malignancies (MESH:D019337), tumorigenesis (MESH:D063646), gastric cancer (MESH:D013274), autoimmune diseases (MESH:D001327), non-alcoholic steatohepatitis (MESH:D005235), hypoxic (MESH:D002534), mammary tumor (MESH:D015674), cytotoxic (MESH:D064420), immune disorders (MESH:D007154), infection (MESH:D007239), viral (MESH:D014777), CRC (MESH:D015179), hematologic (MESH:D006402), tumorigenic (MESH:D002471), deaths (MESH:D003643), hepatic metastasis (MESH:D009362), HCC (MESH:D006528), CD19 B-cell malignancies (MESH:D016393), triple-negative breast cancer (MESH:D064726), breast cancer (MESH:D001943)
- **Chemicals:** paraffin (MESH:D010232), hyaluronan (MESH:D006820), cholesterol- (MESH:D002784), sorafenib (MESH:D000077157), ipilimumab (MESH:D000074324), varlilumab (MESH:C000622120), L-arginine (MESH:D001120), urea (MESH:D014508), isatuximab (MESH:C000599209), calcium (MESH:D002118), formalin (MESH:D005557), nivolumab (MESH:D000077594), lenvatinib (MESH:C531958), LPS (MESH:D008070), lipid (MESH:D008055), daratumumab (MESH:C556306), polyamine (MESH:D011073)
- **Species:** Mus musculus (house mouse, species) [taxon 10090], Homo sapiens (human, species) [taxon 9606]

## Full text

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## References

222 references — full list in the complete paper: https://tomesphere.com/paper/PMC12932472/full.md

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Source: https://tomesphere.com/paper/PMC12932472