{
  "abstract": "Background Hepatocellular carcinoma (HCC) progression can be promoted by tumor cells that adaptively survive extreme metabolic stress. These cells are primarily located in peri-necrotic regions, which experience high oxidative stress. The mechanisms enabling such adaptive survival remain unclear. This study aims to investigate the molecular pathways that support survival in peri-necrotic HCC and explores potential therapeutic targets.Methods Multi-omics analyses of public and in-house HCC datasets identified Neurotensin (NTS) as enriched in peri-necrotic regions. Metabolic stress models were used to explore NTS induction, while transcriptome profiling revealed its downstream targets. In vitro assays assessed the role of NTS in oxidative stress resistance and macrophage polarization. Therapeutic potential of NTS pathway inhibition was tested in a syngeneic subcutaneous HCC model in immunocompetent mice, either alone or combined with anti-PD-1 therapy.Results Peri-necrotic tumor regions were characterized by hypoxia, glucose deprivation, and nutrient stress, indicating a metabolically challenging microenvironment ( IDDF2026-ABS-0236 Figure 1(A,B)). In these regions, NTS was markedly elevated in tumor cells of advanced HCC (IDDF2026-ABS-0236 Figure 1(C)). Mechanistic studies revealed that glucose deprivation triggered NTS expression via the ROS/NF-κB pathway (IDDF2026-ABS-0236 Figure 1(D)). Functionally, NTS enhanced tumor cell survival under oxidative stress by upregulating the antioxidant enzyme AKR1C3, thereby maintaining redox homeostasis (IDDF2026-ABS-0236 Figure 1(E,F)). In parallel, NTS exerted paracrine effects on the tumor immune microenvironment by promoting macrophage polarization toward the M2 phenotype through IL-34 secretion, contributing to an immunosuppressive niche (IDDF2026-ABS-0236 Figure 1(G,H)). In vivo experiments using spontaneous HCC mouse models showed that neurotensin receptor 1 (NTSR1) blockade significantly reduced tumor progression. Importantly, combining NTSR1 inhibition with anti-PD-1 therapy produced a synergistic antitumor effect, highlighting the therapeutic potential of targeting this pathway (IDDF2026-ABS-0236 Figure 1(I)).Conclusions NTS mediates adaptive survival in peri-necrotic HCC through a dual mechanism: maintaining redox homeostasis and remodeling the immune niche. These findings provide a mechanistic rationale for combining NTS inhibition with immune checkpoint blockade and suggest a promising therapeutic strategy for advanced HCC.Abstract IDDF2026-ABS-0236 Figure 1",
  "authors": [
    {
      "affiliations": [
        "Department of Pathology. Beijing Tsinghua Changgung Hospital, School of Clinical Medicine, Tsinghua University, Beijing, China"
      ],
      "name": "Ying Xiao"
    },
    {
      "affiliations": [
        "Hepatopancreatobiliary Center, Beijing Tsinghua Changgung Hospital, School of Clinical Medicine, Tsinghua University, Beijing, China"
      ],
      "name": "Fansen Ji"
    },
    {
      "affiliations": [
        "Department of Pathology. Beijing Tsinghua Changgung Hospital, School of Clinical Medicine, Tsinghua University, Beijing, China"
      ],
      "name": "Jianghui Yang"
    },
    {
      "affiliations": [
        "Department of Pathology. Beijing Tsinghua Changgung Hospital, School of Clinical Medicine, Tsinghua University, Beijing, China"
      ],
      "name": "Huan Li"
    },
    {
      "affiliations": [
        "Department of Pathology. Beijing Tsinghua Changgung Hospital, School of Clinical Medicine, Tsinghua University, Beijing, China"
      ],
      "name": "Bowen Li"
    },
    {
      "affiliations": [
        "Hepatopancreatobiliary Center, Beijing Tsinghua Changgung Hospital, School of Clinical Medicine, Tsinghua University, Beijing, China"
      ],
      "name": "Shizhong Yang"
    },
    {
      "affiliations": [
        "Department of Pathology. Beijing Tsinghua Changgung Hospital, School of Clinical Medicine, Tsinghua University, Beijing, China"
      ],
      "name": "Hongfang Yin"
    }
  ],
  "title": "IDDF2026-ABS-0236 Neurotensin promotes peri-necrotic HCC survival via redox homeostasis and immunosuppressive niche remodeling",
  "uid": "2d2efc40-f4f6-5198-9f8f-3b169ac81212"
}