Enhancing the antitumor phototherapy efficacy of PCSK9 nanobody-engineered bacteria coated with photosensitizer lipids

• Bacteria combined with photothermal liposomes enhance tumor photodynamic therapy. • Activating cGAS-STING-CXCR1/2 axis to reshape tumor immune microenvironment. • Bimodal phototherapy-immunometabolism synergy inhibits tumors growth. • Innovative strategy: bacteria-phototherapy-immunometabolism synergy for cancer. Cancer remains a major health threat, driving the need for new treatments. Phototherapy, a minimally invasive method for targeting tumors, shows promise but faces issues like uneven photosensitizer distribution and heat dispersion, leading to incomplete treatment and tumor recurrence. To address this, we developed genetically engineered bacteria that produce PCSK9 nanobodies and combined them with photothermal liposomes for solid tumor treatment. These engineered bacteria, DPIR@EcN/PCSK9nb, effectively convert light into heat under near-infrared irradiation, boosting the photodynamic impact on tumors while sparing normal tissues. When activated, these bacteria release PCSK9 nanobodies and bacterial antigens, modulating cholesterol levels and activating key signaling pathways in the tumor environment. Photoactivation further triggers the cGAS–STING–NF-κB pathway and regulates the CXCR1/2 axis, reshaping the tumor immune microenvironment, boosting local immune responses, and inducing tumor cell apoptosis. In vivo studies showed significant tumor growth inhibition without major organ toxicity, underscoring the safety and effectiveness of this dual-modality therapy. Combining phototherapy with PCSK9 nanobody-engineered bacteria offers a novel cancer treatment strategy, enhancing anti-tumor effects through coordinated photothermal, immune, and metabolic actions while minimizing side effects, thus providing a promising targeted therapy approach.