Mitochondria-targeting polydopamine-coated nanodrugs for effective photothermal-and chemo-synergistic therapies against lung cancer

Targetingmitochondria via nano platform emerged as an attractive anti-tumor pathway due to the central regulation role in cellar apoptosis and drug resistance.Here,a mitochondria-targeting nanoparticle(TOS-PDA-PEG-TPP)was designed to precisely deliver polydopamine(PDA)as the photothermal agent and alphatocopherol succinate(α-TOS)as the chemotherapeutic drug to the mitochondria of the tumor cells,which inhibits the tumor growth through chemo-and photothermal-synergistic therapies.TOSPDA-PEG-TPP was constructed by coating PDA on the surface of TOS NPs self-assembled byα-TOS,followed by grafting PEGand triphenylphosphonium(TPP)on their surface to prolong the blood circulation time and target delivery of TOS and PDA to the mitochondria of tumor cells.In vitro studies showed that TOS-PDA-PEGTPP could be efficiently internalized by tumor cells and accumulated atmitochondria,resulting in cellular apoptosis and synergistic inhibition of tumor cell proliferation.In vivo studies demonstrated that TOS-PDA-PEG-TPP could be efficiently localized at tumor sites and significantly restrain the tumor growth under NIR irradiation without apparent toxicity or deleterious effects.Conclusively,the combination strategy adopted for functional nanodrugs construction aimed at target-delivering therapeutic agents with different action mechanisms to the same intracellular organelles can be extended to other nanodrugs-dependent therapeutic systems.

Blockading a new NSCLC immunosuppressive target by pluripotent autologous tumor vaccines magnifies sequential immunotherapy

The presence of multiple immunosuppressive targets and insufficient activation and infiltration of cytotoxic T lymphocytes(CTLs)allow tumor cells to escape immune surveillance and disable anti-PD-1/PD-L1 immunotherapy.Nanobiotechnology-engineered autologous tumor vaccines(ATVs)that were camouflaged by tumor cell membrane(TCM)were designed to activate and facilitate CTLs infiltration for killing the unprotected lung tumor cells,consequently realizing the sequential immunotherapy.PDE5 was firstly screened out as a new immunosuppressive target of lung cancer in clinical practice.Immediately afterwards,phosphodiesterase-5(PDE5)and programmed cell death 1 ligand 1(PD-L1)dual-target co-inhibition was proposed to unfreeze the immunosuppressive microenvironment of NSCLC.Systematic studies validated that this ATVs-unlocked sequential immunotherapy after co-encapsulating PDE5 inhibitor and NO donor(i.e.,L-arginine)exerted robust anti-tumor effects through increasing inducible nitric oxide synthase(iNOS)expression,blockading PDE5 pathway and activating systematic immune responses,which synergistically eradicated local and abscopal lung cancers in either orthotopic or subcutaneous models.The pluripotent ATVs that enable PDE5 inhibition and sequential immunotherapy provide a new avenue to mitigate immunosuppressive microenvironment and magnify anti-PD-1/PD-L1 immunotherapy.

Insights into the post-translational modification and its emerging role in shaping the tumor microenvironment

More and more in-depth studies have revealed that the occurrente and development of tumors depend on gene mutation and tumor heterogeneity.The most important manifestation of tumor heterogeneity is the dynamic change of tumor microenvironment(TME)heterogeneity.This depends not only on the tumor cells themselves in the microenvironment where the infiltrating immune cells and matrix together forming an antitumor and/or pro-tumor network.TME has resulted in novel therapeutic in terve ntions as a place beyond tumor beds.The malig nant can cer cells,tumor in filtrate immune cells,angiogenic vascular cells,lymphatic endothelial cells,cancer-associated fibroblastic cells,and the released factors including intracellular metabolites,hormonal signals and inflammatory mediators all contribute actively to cancer progression.Protein post-translational modification(PTM)is often regarded as a degradative mechanism in protein destruction or turnover to maintain physiological homeostasis.Advances in quantitative transcriptomics,proteomics,and nuclease-based gene editing are now paving the global ways for exploring PTMs.In this review,we focus on recent developments in the PTM area and speculate on their importanee as a critical functional readout for the regulation of TME.A wealth of information has been emerging to prove useful in the search for conventional therapies and the development of global therapeutic strategies.

Bottlenecks and opportunities in immunotherapy for glioma:a narrative review

Glioma is the most aggressive brain tumor having invasive ability and a highly heterogeneous phenotype.Many patients with glioma respond poorly to traditional surgery or temozolomide-based chemotherapy.Over the past few decades,developments in immunotherapeutic strategies have provided newer insights into the treatment of gliomas.Immunotherapy is based on the principle of normalization or recovery of T cell-mediated anti-tumor immunoreaction.Different innovative strategies have been used;these include enhancement of immunogenicity by administration of tumor antigens or dendritic cell vaccines,replenishment of cytotoxic T cells by adoptive T cell transfer,repair of exhausted T cells by immune checkpoint inhibitors,and the use of other immune activators such as oncolytic viruses.However,many immunotherapy-based clinical trials did not meet the expected therapeutic endpoints in patients with glioma.Gliomas use unique strategies to generate an immune-suppressive microenvironment;these include limiting immunogenicity and repressing T cell infiltration or activation.This may be addressed by the incorporation of immunotherapy with standard therapy or by use of certain innovative approaches such as tumor-treating fields.In this review,we summarize the updated immunotherapies in glioma and discuss current limitations and future prospects.