Tumor microenvironment-responsive peptide-based molecular probe for cancer immunotherapy

The tumor microenvironment (TME) critically influences immunotherapy efficacy, but existing molecular probes suffer from persistent background signals. Responsive probes activated by TME-specific stimuli offer improved specificity and signal-to-noise ratios, yet their development remains underexplored. We engineered TME-responsive peptide probes for dynamic biomarker monitoring. A pH-activated doxorubicin (DOX) prodrug combined with photodynamic therapy (PDT) and PD-L1 inhibitors (aPD-L1) was developed to induce immunogenic cell death. A granzyme B-responsive probe using FRET and MR/NIRF imaging tracked immunotherapy efficacy, while a comprehensive review analyzed nanomedicine strategies for synergistic immunotherapy. The DOX-PDT-aPD-L1 combination increased CD8+ T-cell infiltration, reduced regulatory T cells, and suppressed primary tumors and metastases. Granzyme B imaging validated cytotoxic T-cell activity, correlating with tumor regression. Nanomedicine strategies highlighted photodynamic/chemotherapy synergy. TME-responsive probes enable precise immunotherapy monitoring and therapeutic optimization. Combinatorial strategies reverse immunosuppressive TME, enhancing antitumor efficacy. Clinical translation requires addressing nanomedicine scalability and toxicity.