Peptide-targeted lipid nanoparticles orchestrating IFN-γ and cisplatin crosstalk eliminate ovarian cancer [RNA-seq]

Ovarian cancer remains refractory to current immunotherapies, largely due to poor tumor targeting, immunosuppressive feedback, and the absence of durable memory responses. Here, we develop a peptide-targeted lipid nanoparticle (ptLNP) platform modified with an FSHR-affinity peptide (Pep LLV) that enables ovarian-directed co-delivery of interferon-gamma (IFN‑γ) mRNA and cisplatin (CDDP). In an orthotopic mouse model, ptLNP-mediated IFN‑γ delivery suppresses tumor progression but upregulates intraovarian PD‑1 expression, creating an adaptive resistance loop that is relieved by co-delivered anti‑PD‑1 antibody. Single-cell RNA sequencing reveals that CDDP eliminates divergent tumor differentiation trajectories and enforces G2/M arrest, which prevents mitotic dilution of the IFN‑γ effector IRF1 and sustains pro-apoptotic signaling. This mechanism is validated by IRF1 gain- and loss-of-function experiments, demonstrating that IRF1 is both sufficient and necessary for the synergistic effect. In T-cell-deficient xenograft models, the IFN‑γ–CDDP combination achieves complete tumor regression, indicating direct cytostatic activity independent of adaptive immunity. Post-treatment IL‑12 boosting further establishes long-term CD4⁺ and CD8⁺ memory T cell responses, conferring protection against tumor re-challenge. Collectively, this study presents a modular platform that orchestrates cytokine therapy, checkpoint blockade, chemotherapy, and memory immunity, providing a mechanistic framework for combinatorial immunotherapy against refractory ovarian cancer.