Research And Application Of X-ray Absorbent For Blocking Immune Escape

Tumor immunotherapy performs tumor therapy by inducing systemic specific immune response,which is the most promising cancer treatment strategy than conventional therapies.Because it coordinates the human’s own immune system to target and eradicate cancer cells,which may lead to lasting antitumor responses and can reduce metastasis and recurrence.However,problems such as low response rate and low efficacy caused by many tumors immune escape mechanisms or immune-related side effects greatly limit the development of immunotherapy.How to achieve efficient tumor immune escape blockade and spatiotemporal controllable activation is the key issue of researchers.X-rays are widely used in biomedical imaging and tumor radiotherapy due to their advantages of strong tissue penetration and controllable radiation parameters.With the development of nanotechnology,many X-ray absorption nanomaterials have been developed to enhance clinical contrast and radiotherapy effects.X-ray absorbers can absorb more X-rays,thereby enhancing the deposition of ionizing radiation energy in the tumor region and reducing the radiation dose.In addition,based on the unique properties of nanomaterials(size effects,high surface area,easy modification,and stability),they can enhance their accumulation in specific tissues or cells and improve their specificity.In addition,nanoscale X-ray absorbers can also be designed as nanodrug vectors for specific response to achieve controlled and local drug release.Therefore,achieving efficient and controllable tumor immune escape inhibition based on X-ray nano-absorbers is highly promising,but has not attracted sufficient research interest.Based on various nanomaterials such as titanium dioxide,gold nanoparticles and metal hybrid materials,we designed and synthesized functional X-ray absorbers for targeted regulation /blocking of tumor cell immune escape from the microenvironment,thus achieving efficient immunotherapy:1.The functional hollow mesoporous titanium dioxide nanoparticles were developed for loading IDOi,which realized the targeted delivery and specific release of IDOi in tumor tissues and relieved the immunosuppressive microenvironment.Under X-ray irradiation,titanium dioxide could kill tumor cells by enhancing radiation deposition and producing abundant ROS.Furthermore,the Mal group modified on the surface of titanium dioxide was exposed in acidic tumor microenvironment and captured tumor specific antigen released when tumor cells died,thereby enhancing antigen presentation and realizing efficient activation of anti-tumor immune response.2.M0 type macrophages were modified by polyvalent aptamers,and the obtained macrophages had low immunogenicity,enhanced in vivo circulation ability and high tumor targeting.After reaching tumor tissues,engineered macrophages could bind to cancer cells through multivalent binding.Under low-dose X-ray irradiation,ROS produced by gold nanocores could induce biocompatible M0 macrophages to transform to anti-tumor M1 type by activating NK-κB pathway,thus activating anti-tumor immune effect in situ.A series of in vitro and in vivo experiments showed that engineered macrophages exhibited great tumor cell targeting and phenotypic polarization induced by X-ray,and could be polarized under X-ray irradiation to secrete a series of anti-cancer factors,thereby killing tumor cells.3.An Au-based nanomodulator was designed and synthesized to regulate the cell communication between tumor and immune cells in tumor tissues to activate anti-tumor immune response in situ.The nanoregulator could bind cancer cells and M2 macrophages in tumor tissues through the modification of tumor targeting aptamer and M2 macrophage targeting peptide on the surface,thereby establishing new intercellular communication between tumor and immune cells.Under low-dose X-ray irradiation,ROS induced tumor-promoting M2-type cells to transform into anti-tumor M1 phenotype in situ.The repolarized macrophages inhibited the growth of primary tumors by phagocytosis and efficient secretion of killer factors,and further inhibited the formation of lung metastatic tumors by immune effect.4.Tumor-related fibroblasts can help tumor cells build defensive "walls" that block large numbers of T cells in the tumor stroma,reducing the efficacy of immune checkpoint drugs.Using the special interaction between gold ions and the biomolecule adenine,we constructed a new type of nanobiocoordination polymer,and further coated the cell membrane of tumor-associated fibroblasts to achieve specificity for tumor-associated fibroblasts targeting.Under X-ray irradiation,the nanopolymer could effectively deposit X-rays and promote the killing of fibroblasts.In addition,the active gold ions in the nanopolymer had a high affinity for sulfur and selenium,which could easily interact with the cysteine or selenocysteine residues of the enzyme,inhibit the activity of the enzyme,and synergistically kill tumor-associated fibroblasts,thereby breaking the "wall" of the tumor,increasing the chance of "hand-to-hand combat" between killer T cells and tumor cells.At the same time,combined with the use of immune blocking inhibitor PD-L1,it can improve the curative effect of radio-immunotherapy as well as reduce the radiation dose and the damage to normal tissues.