Cracking the "Cold Tumor" Barrier in Liver Cancer: How SeekSpace™ Unlocked the Spatial Code of TLS Formation
Release date : Sep 02,2026
Classification : Blog
Cracking the "Cold Tumor" Barrier in Liver Cancer: How SeekSpace™ Unlocked the Spatial Code of TLS Formation
For Research Use Only. Not for use in diagnostic procedures.
Hepatocellular carcinoma (HCC) is a prototypical "immune-cold" tumor with low immunotherapy response rates. Whether mature tertiary lymphoid structures (TLS) form within tumors is a critical determinant of patient outcomes — yet the mechanisms driving TLS biogenesis in HCC have remained poorly understood.
Research Challenges in Spatial Profiling of TLS:
- Spot-based spatial transcriptomics captures mixed-cell signals, requiring computational deconvolution that may be unreliable for rare cell populations such as B cells and dendritic cells within TLS.
- When a capture spot contains both tumor and immune cells, the mixed transcriptome obscures the cellular origin of signaling molecules such as CXCL12.
- Tracing spatial colocalization between ERV neoantigens and B-cell maturation requires cell-level resolution that spot-based platforms cannot directly provide.
Published in Journal of Hepatology, this study by Renji Hospital, Shanghai Jiao Tong University School of Medicine reveals the complete SETDB1–cGAS–STING–CXCL12/ZBP1–ERV regulatory axis driving TLS biogenesis. The core spatial evidence — TLS layered architecture, CXCL12 cell-origin tracing, and ERV–B cell spatial linkage — was generated using SeekSpace™ single-cell spatial transcriptomics.
The SeekSpace™ Solution: Physical Single-Nucleus Resolution
SeekSpace™ takes a fundamentally different approach: tissue sections undergo in situ spatial barcoding of individual nuclei, followed by single-nucleus sequencing. Every data point corresponds to one physically mapped single nucleus — eliminating the need for deconvolution-based inference of cell mixtures. This enables direct attribution of gene expression to specific cell types at specific spatial locations.
| Feature | Conventional Spot-Based ST | SeekSpace™ |
|---|---|---|
| Data unit | Multiple cells per spot | One nucleus = one data point |
| RNA source tracing | Requires deconvolution | Direct cell-of-origin mapping |
| Rare cell detection in TLS | Limited by spot mixing | Direct single-nucleus capture |
Core Insights from the Study | Three Key Findings
Finding 1: TLS high-score regions identified in Setdb1-knockout tumors
Two independent TLS gene signatures scored the spatial data. TLS hotspots appeared only in Setdb1-knockout tumors. SeekSpace™ resolved the canonical TLS architecture — B cells and DCs in the core, T cells and myeloid cells at the periphery — confirming functional TLS formation after SETDB1 deletion.
Finding 2: Tracing the recruitment signal — hepatocytes secrete CXCL12
CXCL12 is a critical B-cell chemoattractant, but identifying its cellular source has been challenging with spot-level resolution. SeekSpace™ localized CXCL12 expression to hepatocytes, cholangiocytes, fibroblasts, and tumor cells. Distance quantification showed B cells were significantly closer to CXCL12-positive hepatocytes in Setdb1-depleted samples, supporting the model that hepatocyte-secreted CXCL12 recruits B cells.
Finding 3: ERV neoantigens drive B-cell maturation in situ
To demonstrate that ERV-derived neoantigens activate B cells, spatial colocalization was essential. SeekSpace™ showed ERV overexpression in tumor cells surrounding TLS areas, and immunoglobulin gene signatures overlapped with ERV-expressing regions — providing spatial evidence that ERV neoantigens contribute to B-cell maturation.
What This Means for Your Research
This study establishes the SETDB1 → cGAS–STING → CXCL12/ZBP1 → ERV regulatory axis in HCC. The core spatial evidence was generated using SeekSpace™, which served as the single-cell-resolution spatial platform in this study. Different spatial transcriptomics platforms serve complementary research needs. SeekSpace™ offers particular strengths in studies that require:
- Physical single-nucleus resolution without deconvolution-based inference
- Direct cell-of-origin tracing for key signaling molecules
- Robust capture even in necrotic microenvironments
- High-confidence spatial evidence for complex tumor–immune tissue studies
- High-quality spatial profiling for clinical patient cohorts
If you are facing challenges with spatial resolution, rare cell detection, or cell-origin tracing in complex tissues, SeekGene can provide technical support for your project.
Shen SJ, Zhou K, Wang CY, et al. Setdb1 represses anti-tumor immunity and tertiary lymphoid structures in hepatocellular carcinoma. Journal of Hepatology. 2026. https://doi.org/10.1016/j.jhep.2026.07.007
Note: This paper is published under a proprietary license ("All rights reserved"); figures may not be reproduced without publisher permission.
Contact
For more information about SeekSpaceTM , please contact us at:
info@seekgene.com
For Research Use Only. Not for use in diagnostic procedures.
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