CD47-targeted liposomal chemotherapy upregulates CD47 expression and induces microsatellite instability which enhances cancer immunotherapy.

Colorectal cancer (CRC) characterized by microsatellite stability (MSS) exhibits a low response rate to immunotherapy, attributed to its inherently poor immunogenicity and the exacerbated immunosuppression. The FOX regimen based on 5-fluorouracil (5-FU) and oxaliplatin (OX), a standard therapy for CRC, paradoxically induces both detrimental upregulation of CD47 and beneficial microsatellite instability (MSI). To capitalize on the beneficial MSI while mitigating the adverse effects of CD47 upregulation, we have developed a CD47 antibody-armored liposome (αL-FOX) loaded with 5-FU and OX. This formulation leverages the chemotherapeutically induced MSI and CD47 upregulation to enhance the immunotherapy efficacy. αCD47 guidance facilitates the positive feedback targeting strategy, selectively delivering αL-FOX to cells that overexpress CD47. The FOX-induced upregulation of CD47 further amplifies this targeted delivery. By blocking the CD47 pathway, αCD47-mediated therapy is expected to reactivate infiltrating immune cells, thereby strengthening innate/adaptive responses. In vivo assays have validated the self-targeting capability of αL-FOX, demonstrating significant tumor suppression, reduced recurrence rates, and extended survival time in metastatic CRC-bearing mice. Notably, these effects are achieved at half the FOX dosage with minimal systemic toxicity. This study highlights the potential of nano-immunotherapeutic drugs that function as chemotherapeutic feedback modulators, offering a promising avenue for heterogeneous and immunotherapy-resistant MSS-CRC.