An isolated monoclonal antibody that specifically binds human Siglec15, or an antigen binding portion thereof. A nucleic acid molecule encoding the antibody or antigen-binding portion thereof, an expression vector, a host cell, and a method for expressing the antibody or antigen binding portion thereof are also provided. The present disclosure further provides an immunoconjugate, a bispecific molecule, a chimeric antigen receptor, an oncolytic virus and a pharmaceutical composition comprising the antibody or antigen-binding portion thereof, as well as a treatment method using the same.