SARS-CoV-2, the virus causing the COVID-19 pandemic, enters human cells through a spike protein that binds to the ACE2 receptor. This process involves receptor-binding domain (RBD) interactions and proteolytic activation by host proteases. The study identifies key entry mechanisms of SARS-CoV-2, including higher hACE2 binding affinity of its RBD compared to SARS-CoV, and furin preactivation of the spike, which enhances entry efficiency. Despite the RBD's high binding affinity, the overall spike has comparable or lower hACE2 binding affinity than SARS-CoV, suggesting the RBD is less accessible. Furin preactivation reduces dependence on target cell proteases, aiding efficient entry. These features contribute to SARS-CoV-2's high infectivity and immune evasion. The study reconciles conflicting reports on SARS-CoV-2 entry and highlights the virus's ability to evade immune surveillance while maintaining high infectivity. Understanding these mechanisms is crucial for developing effective interventions targeting SARS-CoV-2 entry. The findings suggest that SARS-CoV-2's entry is facilitated by furin preactivation and multiple proteases, including TMPRSS2 and cathepsins, which have cumulative effects. The study also clarifies that SARS-CoV-2's RBD, though highly binding to hACE2, is mostly in an inactive conformation, contributing to its immune evasion. These insights provide a foundation for designing interventions that target SARS-CoV-2 entry mechanisms.SARS-CoV-2, the virus causing the COVID-19 pandemic, enters human cells through a spike protein that binds to the ACE2 receptor. This process involves receptor-binding domain (RBD) interactions and proteolytic activation by host proteases. The study identifies key entry mechanisms of SARS-CoV-2, including higher hACE2 binding affinity of its RBD compared to SARS-CoV, and furin preactivation of the spike, which enhances entry efficiency. Despite the RBD's high binding affinity, the overall spike has comparable or lower hACE2 binding affinity than SARS-CoV, suggesting the RBD is less accessible. Furin preactivation reduces dependence on target cell proteases, aiding efficient entry. These features contribute to SARS-CoV-2's high infectivity and immune evasion. The study reconciles conflicting reports on SARS-CoV-2 entry and highlights the virus's ability to evade immune surveillance while maintaining high infectivity. Understanding these mechanisms is crucial for developing effective interventions targeting SARS-CoV-2 entry. The findings suggest that SARS-CoV-2's entry is facilitated by furin preactivation and multiple proteases, including TMPRSS2 and cathepsins, which have cumulative effects. The study also clarifies that SARS-CoV-2's RBD, though highly binding to hACE2, is mostly in an inactive conformation, contributing to its immune evasion. These insights provide a foundation for designing interventions that target SARS-CoV-2 entry mechanisms.