Hybrid prodrug nanoassembly for hypoxia-triggered immunogenic chemotherapy and immune modulation

Tumor hypoxia is a critical driver of cancer progression, metastasis, and therapy resistance, posing significant challenges in effective cancer treatment. Hypoxia-activable prodrugs offer a promising strategy to target tumors in low-oxygen conditions, but their efficacy is often hindered by intrinsic properties and extrinsic cues. In this study, we developed a dual-prodrug nanoassembly system (CPPA) composed of a hypoxia-triggerable camptothecin (CPT)-based dimeric prodrug (CP) and a lipid-conjugated STAT3 antisense oligonucleotide (ASO) prodrug (PA), aiming to enhance tumor-targeted chemotherapy and overcome the immune evasion within the tumor microenvironment. The CPPA self-assemble into stable nanomicelle capable of co-delivering both agents directly to the tumor site, where the hypoxia-triggered release of CPT induces immunogenic cell death (ICD) while STAT3 inhibition enhances immune response. In murine breast cancer models, CPPA demonstrated superior therapeutic efficacy by improving tumor cell killing, promoting immune cell infiltration, and modulating the immunosuppressive tumor microenvironment. This combination therapy not only reversed drug resistance but also prevented the formation of the pre-metastatic niche, significantly inhibiting tumor progression and metastasis. These findings highlight the potential of CPPA as an effective strategy for enhancing cancer immunotherapy, offering a promising approach to address the complex challenges of tumor hypoxia, immune evasion, and resistance to chemotherapy.