In situ induction of multivalent PD-L1 antibody secretion to enhance cancer immunotherapy

Abstract

Immune checkpoint blockade (ICB) therapy has transformed cancer treatment; however, its therapeutic efficacy remains limited, largely due to insufficient intratumoral accumulation of checkpoint-blocking antibodies (e.g., anti-PD-L1) and suboptimal immune activation. To overcome these limitations, we design a multivalent PD-L1 antibody (MV-αPD-L1) that structurally mimics the hexameric architecture of IgM and encapsulates its encoding plasmid into a lipid-assisted polymer nanoparticle. The resulting gene nanomedicine, NP_MV-αPD-L1, enables in situ secretion of MV-αPD-L1 within the tumor microenvironment, achieving high intratumoral antibody concentrations and enhanced PD-L1 binding avidity. Following intravenous administration, NP_MV-αPD-L1 effectively blocks PD-L1, promotes CD8⁺ T-cell infiltration, and enhances cytotoxic T-cell activation, leading to robust tumor inhibition. To further improve tumor specificity, a melanoma-specific tyrosinase (Tyr) promoter is incorporated to generate NP_{Tyr-MV-αPD-L1}, which enables selective intratumoral secretion of MV-αPD-L1 in melanoma. This tumor-restricted antibody production induces potent, localized T-cell activation while minimizing off-target effects, thereby achieving superior therapeutic efficacy with an improved safety profile. Collectively, this strategy reprograms the tumor into a self-sustaining “antibody factory”, providing a versatile and safe platform to amplify ICB efficacy through durable and tumor-specific immune modulation.