Orally administered nanomedicines provide an ideal avenue for cancer immunotherapy, but their efficacy is limited by gastrointestinal absorption challenges, tumor physiological and pathological barriers, and immune evasion mechanisms. In this study, we propose a new strategy to combine the orally transcellularly transported doxorubicin (DOX) nanomedicine with the histone demethylase inhibitor 5-carboxy-8-hydroxyquinoline (IOX1) combination to achieve synergistic chemotherapy and immunotherapy. We demonstrate that IOX1 significantly enhances DOX-loaded poly(2-(N-oxy-N,N-diethylamino)ethylmethacrylate)-poly(ε-caprolactone) nanomicelles (OPDOX) Its transcellular transport ability promotes its transport through different cellular barriers (vill epithelium, endothelium and tumor cells), thereby improving oral absorption, extravascular penetration and tumor penetration. In addition, IOX1 can sensitize chemotherapy, enhance DOX-induced immunogenic cell death, and downregulate programmed cell death ligand 1 (PD-L1), destroy the immune checkpoint mechanism, and synergistically enhance potent anti-tumor immune responses. Therefore, the combination of orally administered OPDOX and IOX1 can effectively inhibit CT26 tumor growth, demonstrating the great potential of enhancing the efficacy of oral nanomedicines in cancer chemotherapy and immunotherapy.

Innovation points:
1. Combined with the histone demethylase inhibitor IOX1, it significantly improves the transcellular transport ability of oral DOX nanomedicines and overcomes the problems of gastrointestinal absorption and tumor barrier.
2. Enhance DOX-induced immunogenic cell death through IOX1 and destroy immune checkpoints through down-regulation of PD-L1, providing synergistic enhancement of chemotherapy and immunotherapy.
3. Use the properties of nanomicelles to improve the absorption, extravascular penetration and tumor penetration of oral drugs, and enhance the effect of drugs in the tumor microenvironment.
4. By regulating the tumor immune microenvironment through IOX1, it breaks through the problem of tumor immune escape and promotes the enhancement of anti-tumor immune response.

Inspiration from scientific research work:
1. Study how to enhance drug delivery between different cell types through drug design, especially in terms of gastrointestinal absorption and tumor penetration, to improve the efficacy of oral drugs.
2. Explore how to overcome tumor drug resistance and enhance anti-tumor effects through combined chemotherapy and immunotherapy, especially in response to microenvironmental regulation and immune escape.
3. Histone demethylase inhibitors such as IOX1 can not only be used to regulate the tumor immune microenvironment, but may also be expanded to the treatment of other immune-related diseases.
4. By combining nanodrug delivery systems with immunomodulatory functions, multifunctional therapeutic platforms with targeted delivery, immune modulation and therapeutic effects can be further developed in the future.

Extension of ideas:
1. Further study the combination of other types of nanocarriers (such as liposomes, polymeric nanoparticles, etc.) with transcellular transport enhancers to achieve efficient delivery of more oral drugs.
2. Only through PD-L1, it can also be combined with other immune checkpoints (such as CTLA-4, TIM-3) for joint inhibition to further improve the effect of immunotherapy.
3. Develop personalized combined chemotherapy and immunotherapy strategies based on different tumor types and patients’ immune microenvironment characteristics to further improve efficacy and safety.
4. In addition to cancer, the potential of this strategy can be explored in other immune diseases or chronic diseases to develop a broader therapeutic platform.
5. Further study how to simultaneously optimize the immune microenvironment during drug delivery and improve tumor immune response and therapeutic effect.

6. Combine nanomedicines, immunomodulators and other therapies (such as gene therapy, photothermal therapy, etc.) to achieve multi-modal collaborative treatment and comprehensively improve the therapeutic effect.

ACS Nano
Pub Date  : 2024-11-29
DOI : 10.1021/acsnano.4c14816

Jing Zhang, Qiuyu Wei, Ying Piao, Shiqun Shao, Zhuxian Zhou, Jianbin Tang, Jiajia Xiang, Youqing Shen