Immune evasion remains a major challenge limiting the efficacy of immunotherapy in triple-negative breast cancer (TNBC). CD24, a dominant \"don\'t eat me\" signal overexpressed on tumor cells, engages Siglec-10 on macrophages to inhibit phagocytosis, thereby facilitating tumor immune escape and representing a promising immune checkpoint target. Herein, we developed a polyethylenimine (PEI)-based nanoparticle system (PDGCS) to deliver a CRISPR/Cas9 plasmid for targeted CD24 editing. PDGCS nanoparticles enabled stable gene delivery and efficient intracellular genome editing, resulting in effective blockade of CD24–Siglec-10 signaling and enhanced phagocytosis by tumor-associated macrophages. In vivo, PDGCS-mediated CRISPR/Cas9 delivery achieved robust CD24 ablation in tumors and significantly inhibited tumor growth. Notably, combination with anti-PD-1 therapy markedly improved antitumor outcomes. The combination treatment also elicited durable immunological memory, protecting surviving mice from tumor rechallenge. Collectively, this study establishes an effective and versatile polymeric CRISPR delivery platform for immune checkpoint modulation, providing a promising strategy to overcome immune resistance and enhance immunotherapeutic outcomes in TNBC.