Chemical messengers have been recognized as signaling molecules involved in regulating various physiological and metabolic activities. Nevertheless, they usually show limited regulatory efficiency due to the complexity of biological processes. Especially for tumor cells, antideath pathways and tumor metastasis are readily activated to resist chemical messenger regulation, further impairing antitumor outcomes. Therefore, it is imperative to develop strategies for tumor eradication with chemical messengers. Herein, a nanomessenger was prepared with signaling transduction cascades to amplify the regulatory activity of chemical messengers and mediate antitumor immunotherapy. Ca2+ and H2S as two chemical messengers were released from nanomessengers to synergistically elevate intracellular Ca2+ stress and mediate subsequent cell death. Meanwhile, zinc protoporphyrin (ZnPP) as a messenger amplifier suppressed the antideath effect of tumor cells. As a result, tumor cells underwent Ca2+-dependent cell death via signaling transduction cascades to release tumor-associated antigens, which further served as an in situ tumor vaccine to activate antitumor immunity. In vivo studies revealed that both primary tumors and distant metastases were markedly eradicated. Furthermore, immunological memory was fabricated to arrest tumor metastasis and recurrence. This work introduces cascade engineering into chemical messengers and thus offers a strategy for amplifying chemical messenger-mediated cellular regulation, which would promote the future development of chemical messenger-mediated immunotherapy.̀.
Keywords: Ca2+-dependent cell death; antitumor immunotherapy; chemical messenger; messenger amplifier; signal cascade.