Decoy antibodies block extracellular HSP70, prevent self-signaling, and inhibit melanoma cell survival.

Melanoma cells secrete melanosomes, large extracellular vesicles that reinforce tumor growth and survival signaling. To determine whether these vesicles elicit functional humoral immunity, we immunized mice with melanoma-derived melanosomes and analyzed the resulting antibody responses. This approach induced B cell expansion and generated antibodies directed against heat shock protein 70 (HSP70) present on the surface of melanosomes. Functionally, anti-HSP70 monoclonal antibodies inhibited growth in murine B16 and human MNT-1 melanoma cells independently of immune effector cells while suppressing key transcriptional programs involved in proliferation. In vivo, passive administration of anti-HSP70 antibodies delayed tumor onset and improved survival in a prophylactic B16 model. Moreover, in patients with metastatic melanoma treated with immune checkpoint blockade, higher serum anti-HSP70 immunoglobulin G (IgG) levels were associated with complete response compared with progressive disease. Together, these findings identify an extracellular vesicle-antibody axis that constrains melanoma survival signaling and has biomarker and therapeutic implications.