{
  "abstract": "Background Mitochondrial antiviral signaling protein (MAVS), a central adaptor in cytosolic RNA sensing, is critical for antitumor innate immunity and maintains mitochondrial homeostasis via its mitochondrial localization. Mitochondrial dysfunction acts as a key driver and amplifier of the senescence-associated secretory phenotype (SASP), a double-edged sword in tumor progression. However, whether tumor-intrinsic MAVS can regulate antitumor immunity via cellular senescence independently of its well-established interferon signaling remains unclear.Methods Our study employed an integrated strategy. Clinically, we profiled MAVS expression and its association with prognosis and immune infiltration in renal tumor specimens. Mechanistic insights into tumor-intrinsic MAVS were gained through a battery of techniques spanning quantitative PCR, immunoblotting, RNA sequencing, senescence and mitochondrial function assays, confocal imaging, immunohistochemical, mass spectrometry, and co-immunoprecipitation. In vivo, we used MAVS-deficient models combined with CD8 + T-cell depletion, programmed cell death protein-1 (PD-1) blockade, or reactive oxygen species (ROS) scavenging by N-acetylcysteine (NAC), with immune infiltration characterized by flow cytometry.Results Clinical evidence links elevated MAVS expression in renal tumors to poor prognosis and diminished CD8 + T-cell infiltration. Strikingly, tumor-intrinsic MAVS deficiency curbed malignant progression by triggering cellular senescence and fostering a permissive niche for CD8+ T-cell activation and recruitment. Mechanistically, MAVS orchestrates mitochondrial integrity by co-localizing with and stabilizing chemokine-like factor-like MARVEL transmembrane domain-containing 6 (CMTM6), thereby shielding it from lysosomal degradation. Disruption of this axis provoked mitochondrial dysfunction and ROS accumulation, culminating in senescence and an SASP marked by chemokine C-C motif ligand 3 (CCL3). Thus, despite dampening canonical innate immune signaling, MAVS deletion unleashed potent antitumor immunity via CCL3-mediated CD8+ T-cell recruitment, an effect abolished by CD8+ T-cell depletion or ROS scavenging with NAC. Leveraging this paradigm, we demonstrated that tumor-specific MAVS deficiency acts synergistically with PD-1 blockade to achieve robust therapeutic efficacy.Conclusions Our findings establish the tumor-intrinsic MAVS/CMTM6/CCL3 axis as a previously unrecognized critical regulator of senescence-driven antitumor immunity in renal carcinoma. Therapeutic targeting of this axis presents a promising strategy to curtail tumor progression and potentiate immunotherapy.",
  "authors": [
    {
      "affiliations": [
        "Senior Department of Urology, Chinese PLA General Hospital, Beijing, China"
      ],
      "name": "Hanfeng Wang"
    },
    {
      "affiliations": [
        "Senior Department of Urology, Chinese PLA General Hospital, Beijing, China"
      ],
      "name": "Yang Fan"
    },
    {
      "affiliations": [
        "Senior Department of Urology, Chinese PLA General Hospital, Beijing, China"
      ],
      "name": "Qiyang Liang"
    },
    {
      "affiliations": [
        "Senior Department of Urology, Chinese PLA General Hospital, Beijing, China"
      ],
      "name": "Wen Tao"
    },
    {
      "affiliations": [
        "Senior Department of Urology, Chinese PLA General Hospital, Beijing, China"
      ],
      "name": "Xinran Chen"
    },
    {
      "affiliations": [
        "Senior Department of Urology, Chinese PLA General Hospital, Beijing, China"
      ],
      "name": "Jichen Wang"
    },
    {
      "affiliations": [
        "Senior Department of Urology, Chinese PLA General Hospital, Beijing, China",
        "School of Medicine, Nankai University, Tianjin, China"
      ],
      "name": "Senming Cao"
    },
    {
      "affiliations": [
        "Senior Department of Urology, Chinese PLA General Hospital, Beijing, China"
      ],
      "name": "Jiali Ye"
    },
    {
      "affiliations": [
        "Senior Department of Urology, Chinese PLA General Hospital, Beijing, China"
      ],
      "name": "Shidong Zuo"
    },
    {
      "affiliations": [
        "Senior Department of Urology, Chinese PLA General Hospital, Beijing, China",
        "School of Medicine, Nankai University, Tianjin, China"
      ],
      "name": "Chi Zhang"
    },
    {
      "affiliations": [
        "Senior Department of Urology, Chinese PLA General Hospital, Beijing, China"
      ],
      "name": "Donglai Shen"
    },
    {
      "affiliations": [
        "Senior Department of Urology, Chinese PLA General Hospital, Beijing, China"
      ],
      "name": "Yu Gao"
    },
    {
      "affiliations": [
        "Senior Department of Urology, Chinese PLA General Hospital, Beijing, China"
      ],
      "name": "Qingbo Huang"
    },
    {
      "affiliations": [
        "Senior Department of Urology, Chinese PLA General Hospital, Beijing, China"
      ],
      "name": "Xin Ma"
    },
    {
      "affiliations": [
        "Senior Department of Urology, Chinese PLA General Hospital, Beijing, China"
      ],
      "name": "Xu Zhang"
    },
    {
      "affiliations": [
        "Senior Department of Urology, Chinese PLA General Hospital, Beijing, China"
      ],
      "name": "Yan Huang"
    },
    {
      "affiliations": [
        "Senior Department of Traditional Chinese Medicine, Chinese PLA General Hospital, Beijing, China"
      ],
      "name": "Minghui Yang"
    }
  ],
  "title": "MAVS/CMTM6 axis couples mitochondrial homeostasis to immunogenic senescence via CCL3-driven T-cell recruitment in renal carcinoma",
  "uid": "cba160fc-8385-5c8d-9780-2f1da3cf2604"
}