A tumor-targeting porphyrin-micelle with enhanced STING agonist delivery and synergistic photo-/immuno- therapy for cancer treatment

The activation of STING pathway has emerged as a promising strategy in cancer immunotherapy. However, challenges associated with unfavorable physicochemical properties and potential off-target toxicities have limited the application of STING agonists. Here, we develop an amphiphilic and cationic charged porphyrin-polymer to electrostatically load the STING agonist (MSA-2) within a micellar structure, thereby enhancing carrier compatibility and drug-loading content of MSA-2. Additionally, tumor-targeting ligands were functionalized onto the micelle to enhance specificity for tumor cells, aiming to significantly improve tumor accumulation while minimizing undesirable toxicity. The resultant tumor-targeting porphyrin micelle (TPC@M) seamlessly integrates three therapeutic mechanisms: i) tumor ablation via phototherapy; ii) robust activation of the STING pathway by MSA-2; iii) synergistic photo-/immuno- stimulations. TPC@M efficiently ablates primary tumors through phototherapy and further activates adaptive immune responses synergistically with MSA-2-induced innate immunity to suppress metastasis and prevent recurrence. Overall, we transformed a delivery-compromised therapeutic into a precise, stable, and safe nanomedicine that unleashes synergistic immunotherapeutic effects.

Statement of significance

This study addresses the urgent need for an efficient delivery system to fully harness the potential of the STING agonist MSA-2 in cancer immunotherapy. The cGAS-STING pathway plays a critical role in modulating anti-tumor immunity; however, the clinical application of MSA-2 has been hindered by its poor physicochemical properties and off-target effects. Our innovative approach introduces a tumor-targeting porphyrin-based polymeric micelle (TPC@M) that efficiently encapsulates MSA-2, overcoming compatibility issues associated with traditional nanocarriers. The TPC@M not only exhibits enhanced tumor targeting and reduced toxicity but also integrates phototherapy with immunotherapy, providing a synergistic strategy for cancer treatment. Our in vivo findings using 4T1 breast cancer mouse models demonstrate significant inhibition of tumor growth and prevention of metastasis, accompanied by a robust and long-lasting immune response.