Dual‐Targeted Lipid Nanotherapeutic Boost for Chemo‐Immunotherapy of Cancer

Abstract Chemo‐immunotherapy is a combination of “standard‐of‐care” chemotherapy with immunotherapy and it is considered the most advanced therapeutic modality for various types of cancers. However, many cancer patients still poorly respond to current regimen of chemo‐immunotherapy and suggest nanotherapeutics as a boosting agent. Recently, heme oxygenase‐1 (HO1) is shown to act as an immunotherapeutic molecule in tumor myeloid cells, in addition to general chemoresistance function in cancer cells suggesting that HO1‐targeted therapeutics can become a novel, optimal strategy for boosting chemo‐immunotherapy in the clinic. Currently the available HO1‐inhibitors demonstrate serious adverse effects in clinical use. Herein, tumor myeloid cell‐ and cancer cell‐dual targeted HO1‐inhibiting lipid nanotherapeutic boost (T‐iLNTB) is developed using RNAi‐loaded lipid nanoparticles. T‐iLNTB‐mediated HO1‐inhibition sensitizes cancer cells to “standard‐of‐care” chemotherapeutics by increasing immunogenic cell death, and directly reprograms tumor myeloid cells with distinguished phenotype. Furthermore, tumor myeloid cell reprogramming by T‐iLNTB induces CD8⁺ cytotoxic T cell recruitment, which drives “Cold‐to‐Hot” transition and correlates with improved responsiveness to immune checkpoint inhibitor in combination therapy. Finally, ex vivo study proves that HO1‐inhibition directly affects tumor macrophage differentiation. This study demonstrates the potential of T‐iLNTB as a novel therapeutic modality for boosting chemo‐immunotherapy.