{
  "abstract": "Background Oncolytic virus M1 (OVM), a naturally occurring alphavirus, has demonstrated potent antitumor activity in various solid tumor models by inducing immunogenic cell death and activating CD8 + T cells. However, its in vivo efficacy varies widely, and resistance mechanisms remain poorly understood. Tumor-associated macrophages (TAMs), key immunosuppressive cells within the tumor microenvironment, may limit OVM therapeutic potential.Methods We investigated the role of TAMs in OVM resistance using multiple syngeneic mouse tumor models (MC38 colorectal cancer, KPC1199 pancreatic cancer, RM1 prostate cancer, and B16F10 melanoma). TAMs were depleted using clodronate liposomes or CSF1R (Colony Stimulating Factor 1 Receptor) antibodies. Flow cytometry, mass cytometry, quantitative reverse transcription-PCR, and transcriptomic sequencing were employed to assess TAMs infiltration, viral load, and immune responses. CD8 + T cells were selectively depleted to determine their functional relevance.Results TAMs infiltration was positively correlated with resistance to OVM across tumor models. Depletion of TAMs increased intratumoral viral load and promoted accumulation of GZMB + CD8+ T cells. RNA sequencing analysis revealed upregulation of antiviral and T-cell immune pathways in TAMs-depleted tumors. Importantly, the therapeutic benefit of TAMs depletion was abrogated on CD8+ T-cell depletion, confirming their essential role in mediating OVM efficacy. In both OVM non-responsive and responsive tumors, TAMs depletion enhanced OVM-mediated tumor suppression and survival.Conclusions TAMs, particularly M1-like subsets, play a critical role in mediating resistance to OVM therapy by reducing viral persistence and suppressing CD8 + T-cell responses. Targeting TAMs significantly improves the antitumor efficacy of OVM in solid tumors. These findings support the development of TAMs-targeted combination strategies to optimize oncolytic virotherapy.",
  "authors": [
    {
      "affiliations": [
        "Department of Pharmacology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, Guangdong, China"
      ],
      "name": "Xuanming Liang"
    },
    {
      "affiliations": [
        "Sun Yat-sen University Sixth Affiliated Hospital Reproductive Medicine Center, Guangzhou, Guangdong, China"
      ],
      "name": "Jingjie Li"
    },
    {
      "affiliations": [
        "Department of Pharmacology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, Guangdong, China"
      ],
      "name": "Jiehong Chen"
    },
    {
      "affiliations": [
        "Department of Pharmacology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, Guangdong, China"
      ],
      "name": "Chaoxin Chen"
    },
    {
      "affiliations": [
        "Department of Pharmacology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, Guangdong, China"
      ],
      "name": "Honghui Li"
    },
    {
      "affiliations": [
        "Department of Pharmacology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, Guangdong, China"
      ],
      "name": "Caixin Yan"
    },
    {
      "affiliations": [
        "Sun Yat-sen University Cancer Center Department of Neurosurgery and Neuro Oncology, Guangzhou, Guangdong, China"
      ],
      "name": "Cui Guo"
    },
    {
      "affiliations": [
        "Department of Neurosurgery/Neuro-oncology, Sun Yat-sen University Cancer Center, Guangzhou, China"
      ],
      "name": "Yu Han"
    },
    {
      "affiliations": [
        "Department of Pharmacology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, Guangdong, China"
      ],
      "name": "Wenfeng Liu"
    },
    {
      "affiliations": [
        "Department of Neurosurgery/Neuro-oncology, Sun Yat-sen University Cancer Center, Guangzhou, China"
      ],
      "name": "Ke Sai"
    },
    {
      "affiliations": [
        "Department of Pharmacology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, Guangdong, China"
      ],
      "name": "Yuan Lin"
    },
    {
      "affiliations": [
        "Sun Yat-Sen University, Guangzhou, Guangdong, China"
      ],
      "name": "Guangmei Yan"
    },
    {
      "affiliations": [
        "Department of Pharmacology, Sun Yat-Sen University, Guangzhou, China"
      ],
      "name": "Wenbo Zhu"
    },
    {
      "affiliations": [
        "Department of Infectious Diseases, Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong, China"
      ],
      "name": "Ying Liu"
    }
  ],
  "title": "TAMs-mediated resistance to oncolytic virus M1 in solid tumors",
  "uid": "20c0ba27-09e6-5166-a118-2dc278438b18"
}