{
  "abstract": "Background Immune checkpoint inhibitors (ICIs) have revolutionized cancer therapy, with efficacy closely linked to tumor immunophenotype. ‘Hot’ tumors, characterized by high T cell infiltration, interferon-γ signaling, PD-L1 expression, and tumor mutational burden (TMB), respond favorably to ICIs. In contrast, ‘cold’ tumors exhibit limited CD8 + T cell infiltration, low TMB, reduced antigen presentation, and elevated immunosuppressive cell populations, contributing to poor ICI responsiveness. As combination therapies and tumor microenvironment (TME) modulation gain prominence, advanced syngeneic models are needed to better recapitulate therapeutic complexity.Methods and Results Following IACUC- and AAALAC-compliant protocols, we evaluated various syngeneic mouse models for ICI efficacy and response heterogeneity. In the CT26 colon carcinoma model, combination radiotherapy and immunotherapy significantly reduced tumor burden and improved survival. In the CT26-hHER2 model, combining ICIs with antibody-drug conjugates (ADCs) enhanced antitumor efficacy and survival, addressing resistance and toxicity limitations of ADC monotherapy. While ID8 tumors (subcutaneous and orthotopic) displayed minimal ICI responsiveness, the intraperitoneal model showed variable responses, with some mice benefiting from PD-1 blockade. Tumor implantation site influenced ICI efficacy: intracerebroventricular GL261 gliomas elicited moderate responses consistent with clinical glioblastoma outcomes, in contrast to heightened responses in subcutaneous models. Notably, the CT26 model responded strongly to ICI treatment in subcutaneous, brain (intracerebroventricular), and liver (intrasplenic) models, but exhibited a ‘cold’ tumor phenotype and reduced response when implanted orthotopically in the colon.Conclusions We have established and validated multiple syngeneic models that accurately reflect differential ICI responses in hot versus cold tumor contexts and under various implantation conditions. These models provide a robust platform for preclinical evaluation of ICI monotherapies and combination strategies, underscoring the critical role of tumor phenotype and anatomical context in immunotherapeutic outcomes.",
  "authors": [
    {
      "affiliations": [
        "ChemPartner, Shanghai, China"
      ],
      "name": "Ying Gu"
    },
    {
      "affiliations": [
        "ChemPartner, South San Francisco, CA, USA"
      ],
      "name": "Patrick Wood"
    },
    {
      "affiliations": [
        "ChemPartner, South San Francisco, CA, USA"
      ],
      "name": "Robert Bi"
    },
    {
      "affiliations": [
        "ChemPartner, Shanghai, China"
      ],
      "name": "Qiong Wang"
    },
    {
      "affiliations": [
        "ChemPartner, Copenhagen, Denmark"
      ],
      "name": "Cathrine Beatty"
    },
    {
      "affiliations": [
        "ChemPartner, Copenhagen, Denmark"
      ],
      "name": "Amanda K Miles"
    },
    {
      "affiliations": [
        "ChemPartner, Shanghai, China",
        "ChemPartner, Copenhagen, Denmark"
      ],
      "name": "Yinfei Yin"
    },
    {
      "affiliations": [
        "ChemPartner, Shanghai, China"
      ],
      "name": "Qikuan Chen"
    }
  ],
  "title": "413 Modeling immunotherapy: syngeneic tumor models reveal context-dependent responses to checkpoint inhibition",
  "uid": "d50a8d07-8475-5c14-85b8-5e00ecb0da36"
}