This study is the first to reveal that oncolytic avian reovirus (ARV) modulates the IKK/NF-κB signaling through the Hsp90-Cdc37, T-complex protein-1 ring complex (TRiC)/Hsc70, and TRiC-phosducin-like protein 1 (PhLP1) chaperone complexes, thereby inducing chaperone-mediated autophagy in mammalian and human cancer lines (referred to as Vero and A549). Here, HSPA8 is linked to cancer.