The present disclosure provides a method of managing cytokine release syndrome (CRS) in a subject undergoing immunotherapy treatment, the method comprises administering to the subject an amount of an A3 adenosine receptor (A3AR) ligand effective to manage one or more of (i) level of at least one inflammatory cytokine and (ii) at least one CRS symptom； wherein said management is without significantly affecting said immunotherapy treatment. Also provided by the present disclosure is an A3 AR ligand and a composition comprising the ligand for use in the management of cytokine release syndrome (CRS) in a subject undergoing immunotherapy treatment, said management comprises one or more of (i) managing level of at least one inflammatory cytokine and (ii) managing at least one CRS symptom； wherein said management is without significantly affecting said immunotherapy treatment.
