{
  "abstract": "Macrophage-directed immunotherapy, exemplified by blocking the CD47-signal regulatory protein α (SIRPα) axis, can eliminate tumors by unleashing phagocytosis. However, such approaches often fail to generate durable antitumor immunity, revealing a disconnect between innate activation and effective T cell responses. Here, we identify proprotein convertase subtilisin/kexin type 9 (PCSK9) as an adaptive resistance factor induced by macrophage checkpoint blockade. Tumor-derived PCSK9 promotes lysosomal degradation of major histocompatibility complex class I (MHC-I) in macrophages, impairing antigen cross-presentation and CD8+ T cell priming—thus showing how phagocytosis-targeted therapies can paradoxically suppress adaptive immunity. To overcome this, we engineer bispecific fusion proteins co-targeting the CD47-SIRPα checkpoint and the PCSK9-MHC-I axis, among which SIRPαD1-αPCSK9 is optimal. Dual targeting synergistically enhances phagocytosis, preserves antigen cross-presentation, and reprograms tumor microenvironment toward an immunostimulatory state. Consequently, SIRPαD1-αPCSK9 activates innate and adaptive antitumor immunity, achieving potent tumor control with improved safety. These findings uncover a resistance mechanism to macrophage-centered cancer immunotherapy and establish a dual-targeting strategy bridging phagocytosis and T cell activation.",
  "abstract_shown": true,
  "affiliations": [
    "School of Pharmaceutical Sciences & Shanghai Engineering Research Center of Immunotherapeutics, Fudan University, Shanghai, China",
    "Quzhou Fudan Institute, 108 Minjiang Avenue, Kecheng District Quzhou, Zhejiang, China",
    "Department of Research and Development, Shanghai Proton and Heavy Ion Center, Fudan University Cancer Hospital, Shanghai, China",
    "Department of Cancer Biology, Abramson Family Cancer Research Institute, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA"
  ],
  "article_type": "research article",
  "arxiv": null,
  "author_total": 13,
  "authors": [
    {
      "affs": [
        0,
        1
      ],
      "name": "Caili Xu"
    },
    {
      "affs": [
        0,
        1
      ],
      "name": "Kaicheng Zhou"
    },
    {
      "affs": [
        0
      ],
      "name": "Xiaozhi Hu"
    },
    {
      "affs": [
        0
      ],
      "name": "Yanyang Nan"
    },
    {
      "affs": [
        2
      ],
      "name": "Yun Sun"
    },
    {
      "affs": [
        0
      ],
      "name": "Zihan Dou"
    },
    {
      "affs": [
        0
      ],
      "name": "Rui Zhou"
    },
    {
      "affs": [
        0
      ],
      "name": "Wenjing Xue"
    },
    {
      "affs": [
        0
      ],
      "name": "Qinchao Hu"
    },
    {
      "affs": [
        0
      ],
      "name": "Xiting Huang"
    },
    {
      "affs": [
        3
      ],
      "name": "Xianxin Hua"
    },
    {
      "affs": [
        0,
        1
      ],
      "name": "Dianwen Ju"
    },
    {
      "affs": [
        0,
        1
      ],
      "name": "Xuyao Zhang"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/6cfvtr5642nx0.bib",
  "cited_by": 0,
  "doi": "10.1016/j.xcrm.2026.103087",
  "fulltext_url": "https://pmc.ncbi.nlm.nih.gov/articles/PMC13710386/",
  "id": "6cfvtr5642nx0",
  "issns": [
    "2666-3791"
  ],
  "landing_url": "https://doi.org/10.1016/j.xcrm.2026.103087",
  "language": "en",
  "licence": "CC-BY-NC-ND-4.0",
  "licence_label": "CC BY-NC-ND 4.0",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by-nc-nd/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "heading",
      "Article"
    ],
    [
      "openalex",
      "2403|Phagocytosis and Immune Regulation"
    ]
  ],
  "openalex": "W7220417389",
  "pdf_url": null,
  "pmcid": "PMC13710386",
  "pmid": "42833217",
  "published": "2026-10-05",
  "publisher": "Elsevier",
  "ris": "https://research.draconitic.com/paper/6cfvtr5642nx0.ris",
  "sources": [
    {
      "first_seen": "2026-10-31T12:21:22Z",
      "native_id": "PMC13710386",
      "source": "pmc",
      "url": "https://doi.org/10.1016/j.xcrm.2026.103087"
    }
  ],
  "subjects": [
    {
      "field": "biology",
      "origin": "openalex:2403|Phagocytosis and Immune Regulation",
      "subfield": "immunology"
    }
  ],
  "title": "Bridging innate and adaptive immunity: A bispecific SIRPαD1-αPCSK9 fusion protein reprograms macrophages for durable tumor clearance",
  "title_text": "Bridging innate and adaptive immunity: A bispecific SIRPαD1-αPCSK9 fusion protein reprograms macrophages for durable tumor clearance",
  "type": "peer-reviewed",
  "updated_at": "2026-10-31T12:21:22Z",
  "url": "https://research.draconitic.com/paper/6cfvtr5642nx0",
  "venue": "Cell Reports Medicine",
  "versions": []
}