<p>Triple-negative breast cancer therapy is challenging due to its limited immune response and weak tumor immunogenicity. Here, we constructed near infrared (NIR)-mediated nanodrugs with endosomal escape capability to modulated the innate/acquired immune response and gene silencing through the STING-pyroptosis self-cycling amplification/functional nucleic acid enzymes (FNAzymes) cleavage. The nanodrugs are first captured by tumor cell lysosomes. Importantly, reactive oxygen species generated from nanodrugs under NIR light irradiation disrupt the lipid membrane of lysosomes, thereby promoting the endosomal escape of the nanodrugs and allowing them enter the cytoplasm. Subsequently, Mn²⁺ released from nanodrugs activates the STING pathway and induces pyroptosis via NLRP3-Caspase-1-GSDMD pathway. Interestingly, the occurrence of pyroptosis leads to mitochondrial membrane remodeling and mitochondrial DNA release, which in turn enhanced STING activation and forming of STING-pyroptosis self-recycling amplification, leading to the innate/acquired immune response of the tumor. Meanwhile, Mn²⁺ acted as a cofactor of FNAzymes to activate the gene-silencing function of FNAzymes, realizing highly specific and endogenous long-term regulation. Finally, nanodrugs achieved efficient tumor inhibition by regulating the innate/acquired immune response/gene silencing. This study demonstrates a strategy to construct STING-pyroptosis self-cycling amplification combined with FNAzymes cleavage, which provide ideas for future efficient and durable tumor therapy.</p>