A mature tertiary lymphoid structure-associated spatial niche is inversely associated with ACC1-related lipid metabolism in neoadjuvant-treated hepatocellular carcinoma.
6 affiliations
- 1Department of Gastroenterology, Rudong People's Hospital, Affiliated Rudong Hospital of Xinglin College, Nantong University, Nantong, China.
- 2Department of Endoscopy Center, Wusong Branch of Zhongshan Hospital, Fudan University, Shanghai, China.
- 3Department of Transplantation, Xinhua Hospital affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China.
- 4Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China. Electronic address: [email protected].
- 5Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China. Electronic address: [email protected].
- 6Department of Transplantation, Xinhua Hospital affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China. Electronic address: [email protected].
Abstract
Tumor heterogeneity in hepatocellular carcinoma (HCC) is shaped by spatially organized immune and metabolic ecosystems that may influence therapeutic response. However, how mature tertiary lymphoid structure (TLS) niches relate to tumor metabolic heterogeneity remains poorly defined. We integrated seven 10x Visium sections from patients with locally advanced HCC treated with neoadjuvant cabozantinib plus nivolumab, a single-cell reference atlas, three independent bulk cohorts, and a pathological validation cohort of 69 HCC specimens. Reference-based deconvolution and neighborhood-composition clustering identified eleven recurrent multicellular niches, including a B-cell-, plasma-cell-, and T-cell-enriched mature TLS-associated niche (Niche5). Niche5 showed greater spatial aggregation in pathological responders, accompanied by stronger CCL21-CCR7, CXCL13-CXCR5, and CCL19-CCR7 signaling. Within Niche5, fatty-acid metabolism was inversely correlated with the TLS program (Spearman r=-0.35) and chemokine-ligand expression. A six-gene Niche5-derived signature selected using a machine-learning framework stratified overall survival across three independent cohorts. Among fatty-acid-metabolism enzymes, ACACA, encoding ACC1, showed the most reproducible negative association with TLS chemokines, antigen presentation, CD8-positive T-cell programs, and survival. Multiplex immunofluorescence and immunohistochemistry confirmed mature TLS architecture and demonstrated spatial separation between TLS and ACC1-, FABP5-, and PLIN2-enriched tumor compartments. In the validation cohort, TLS-positive tumors showed lower ACC1, FABP5, and PLIN2 expression but higher CCL21, CXCL13, and CCR7 expression, while high ACC1 expression was independently associated with reduced TLS positivity. Together, these findings provide exploratory evidence of immune-metabolic spatial heterogeneity in HCC and identify an inverse, associative relationship between mature TLS organization and ACC1-related lipid metabolism.
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BibTeX
@article{wang2026mature,
title = {{A mature tertiary lymphoid structure-associated spatial niche is inversely associated with ACC1-related lipid metabolism in neoadjuvant-treated hepatocellular carcinoma.}},
author = {Ronghua Wang and Biao Shen and Yanan Wu and Shuai Zhao and Wenhao Xu and Wangrui Liu and Jian Wang},
journal = {Translational oncology},
year = {2026},
month = oct,
doi = {10.1016/j.tranon.2026.103062},
url = {https://europepmc.org/article/MED/42858645},
note = {CC BY-NC-ND},
}
RIS
TY - JOUR
TI - A mature tertiary lymphoid structure-associated spatial niche is inversely associated with ACC1-related lipid metabolism in neoadjuvant-treated hepatocellular carcinoma.
AU - Ronghua Wang
AU - Biao Shen
AU - Yanan Wu
AU - Shuai Zhao
AU - Wenhao Xu
AU - Wangrui Liu
AU - Jian Wang
PY - 2026
DA - 2026/10/10
JO - Translational oncology
DO - 10.1016/j.tranon.2026.103062
UR - https://europepmc.org/article/MED/42858645
AB - Tumor heterogeneity in hepatocellular carcinoma (HCC) is shaped by spatially organized immune and metabolic ecosystems that may influence therapeutic response. However, how mature tertiary lymphoid structure (TLS) niches relate to tumor metabolic heterogeneity remains poorly defined. We integrated seven 10x Visium sections from patients with locally advanced HCC treated with neoadjuvant cabozantinib plus nivolumab, a single-cell reference atlas, three independent bulk cohorts, and a pathological validation cohort of 69 HCC specimens. Reference-based deconvolution and neighborhood-composition clustering identified eleven recurrent multicellular niches, including a B-cell-, plasma-cell-, and T-cell-enriched mature TLS-associated niche (Niche5). Niche5 showed greater spatial aggregation in pathological responders, accompanied by stronger CCL21-CCR7, CXCL13-CXCR5, and CCL19-CCR7 signaling. Within Niche5, fatty-acid metabolism was inversely correlated with the TLS program (Spearman r=-0.35) and chemokine-ligand expression. A six-gene Niche5-derived signature selected using a machine-learning framework stratified overall survival across three independent cohorts. Among fatty-acid-metabolism enzymes, ACACA, encoding ACC1, showed the most reproducible negative association with TLS chemokines, antigen presentation, CD8-positive T-cell programs, and survival. Multiplex immunofluorescence and immunohistochemistry confirmed mature TLS architecture and demonstrated spatial separation between TLS and ACC1-, FABP5-, and PLIN2-enriched tumor compartments. In the validation cohort, TLS-positive tumors showed lower ACC1, FABP5, and PLIN2 expression but higher CCL21, CXCL13, and CCR7 expression, while high ACC1 expression was independently associated with reduced TLS positivity. Together, these findings provide exploratory evidence of immune-metabolic spatial heterogeneity in HCC and identify an inverse, associative relationship between mature TLS organization and ACC1-related lipid metabolism.
SN - 1936-5233
ER -