TAMs-mediated resistance to oncolytic virus M1 in solid tumors

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.

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.

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.

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.