BACKGROUND: The COVID-19 pandemic continues to affect the world in 2025. The rapid mutation of SARS-CoV-2 results in breakthrough infections and diminishes the efficacy of vaccines and anti-viral drugs. The severity of the disease varies across different variants, and the underlying mechanisms driving these differences remain unclear. This study explores the relationship between different Spike variants and cytotoxicity, aiming to determine whether the humanized decoy receptor ACE2-Fc can neutralize spikes from diverse variants, offering a solution to overcome rapid mutating SARS-CoV-2 induced immune escape. METHODS: We co-cultured 293 T-ACE2 cells with 293 T cells transfected with various Spike protein variants or used H1650-ACE2 cells transfected with these Spike variants. This allowed us to observe the effects of different Spike mutations, specifically focusing on cell fusion, cytotoxicity, and cytokine release from human peripheral blood mononuclear cells. Flow cytometry is employed to determine if ACE2-Fc can recognize different Spike variants. We also assess the ability of ACE2-Fc to inhibit infection, cell fusion, cytotoxicity, and cytokine release through pseudovirus infections or Spike protein transfections. Additionally, we use actual viruses from SARS-CoV-2 patients to validate the impacts of Spike mutations and the effectiveness of ACE2-Fc. Furthermore, human plasma is utilized to evaluate ACE2-Fc's capability to inhibit Spike-induced clot formation. RESULTS: We found that different Spike variants, particularly those with enhancements at the S2' site, increased cell-cell fusion capability, which correlated positively with cytotoxicity and cytokine IL-6 and TNF-α released from PBMCs. ACE2-Fc recognized spikes from wide-range of variants, including wild type, Alpha, Delta, Delta plus, Lambda, BA.2, BA.2.75, BA.5, BF.7, BQ.1, XBB.1, JN.1, KP.2, and KP.3, and effectively prevented these spike-expressing pseudo-viruses from entering host cells. Crucially, ACE2-Fc can prevent spike-induced cell fusion, thereby reducing subsequent cytotoxicity and the release of IL-6 and TNF-α from PBMCs. ACE2-Fc also effectively reduces plasma clot formation induced by trimeric spike proteins. CONCLUSIONS: These findings demonstrated that ACE2-Fc could effectively combat the infection of rapidly mutating SARS-CoV-2, providing a potential solution to overcome immune evasion.