Therapeutic challenge for immunotherapy targeting cold colorectal cancer: A narrative review

Cold colorectal tumors are not likely to trigger a robust immune response and tend to suppress the immune response.There may be three reasons.First,the complex tumor microenvironment of cold colorectal cancer(CRC)leads to tolerance and clearance of immunotherapy.Second,the modification and concealment of tumor-specific targets in cold CRC cause immune escape and immune response interruption.Finally,the difference in number and function of immune cell subsets in patients with cold CRC makes them respond poorly to immunotherapy.Therefore,we can only overcome the challenges in immunotherapy of cold CRC through in-depth research and understanding the changes and mechanisms in the above three aspects of cold CRC.

Targeted Local Immunization in Scale-Free Peer-to-Peer Networks

The power-law node degree distributions of peer-to-peer overlay networks make them extremely robust to random failures whereas highly vulnerable under intentional targeted attacks. To enhance attack survivability of these networks, DeepCure, a novel heuristic immunization strategy, is proposed to conduct decentralized but targeted immunization. Different from existing strategies, DeepCure identifies immunization targets as not only the highly-connected nodes but also the nodes with high availability and/or high link load, with the aim of injecting immunization information into just right targets to cure. To better trade off the cost and the efficiency, DeepCure deliberately select these targets from 2-local neighborhood, as well as topologically-remote but semantically-close friends if needed. To remedy the weakness of existing strategies in case of sudden epidemic outbreak, DeepCure is also coupled with a local-hub oriented rate throttling mechanism to enforce proactive rate control. Extensive simulation results show that DeepCure outperforms its competitors, producing an arresting increase of the network attack tolerance, at a lower price of eliminating viruses or malicious attacks.

System Recovery-Aware Virus Propagation Model and Its Steady-State Analysis

Network structures and human behaviors are considered as two important factors in virus defense currently. However, due to ignorance of network security, normal users usually take simple activities, such as reinstalling computer system, or using the computer recovery system to clear virus. How system recovery influences virus spreading is not taken into consideration currently. In this paper, a new virus propagation model considering the system recovery is proposed first, and then in its steady-state analysis, the virus propagation steady time and steady states are deduced. Experiment results show that models considering system recovery can effectively restrain virus propagation. Furthermore, algorithm with system recovery in BA scale-free network is proposed. Simulation result turns out that target immunization strategy with system recovery works better than traditional ones in BA network.

Engineered Cancer Nanovaccines:A New Frontier in Cancer Therapy

Vaccinations are essential for preventing and treating disease,especially cancer nanovaccines,which have gained considerable interest recently for their strong anti-tumor immune capabilities.Vaccines can prompt the immune system to generate antibodies and activate various immune cells,leading to a response against tumor tissues and reducing the negative effects and recurrence risks of traditional chemotherapy and surgery.To enhance the flexibility and targeting of vaccines,nanovaccines utilize nanotechnology to encapsulate or carry antigens at the nanoscale level,enabling more controlled and precise drug delivery to enhance immune responses.Cancer nanovaccines function by encapsulating tumor-specific antigens or tumor-associated antigens within nanomaterials.The small size of these nanomaterials allows for precise targeting of T cells,dendritic cells,or cancer cells,thereby eliciting a more potent anti-tumor response.In this paper,we focus on the classification of carriers for cancer nanovaccines,the roles of different target cells,and clinically tested cancer nanovaccines,discussing strategies for effectively inducing cytotoxic T lymphocytes responses and optimizing antigen presentation,while also looking ahead to the translational challenges of moving from animal experiments to clinical trials.

Biological drug and drug delivery-mediated immunotherapy

The initiation and development of major infammatory diseases,i.e.,cancer,vascular infammation,and some autoimmune diseases are closely linked to the immune system.Biologics-based immunotherapy is exerting a critical role against these diseases,whereas the usage of the immunomodulators is always limited by various factors such as susceptibility to digestion by enzymes in vivo,poor penetration across biological barriers,and rapid clearance by the reticuloendothelial system.Drug delivery strategies are potent to promote their delivery.Herein,we reviewed the potential targets for immunotherapy against the major infammatory diseases,discussed the biologics and drug delivery systems involved in the immunotherapy,particularly highlighted the approved therapy tactics,and finally offer perspectives in this feld.

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.

A new approach for the treatment of CLL using chlorambucil/hydroxychloroquine-loaded anti-CD20 nanoparticles

Current approaches for the treatment of chronic lymphocytic leukemia （CLL） have greatly improved the prognosis for survival, but some patients remain refractive to these therapeutic regimens. Hence, in addition to reducing the long-term side- effects of therapeutics for all leukemia patients, there is an urgent need for novel therapeutic strategies for difficult-to-treat leukemia cases. Due to the cytotoxicity of drugs, the major challenge currently is to deliver the therapeutic agents to neoplastic cells while preserving the viability of non-malignant ceils. In this study, we propose a therapeutic approach in which high doses of hydroxychloroquine and chlorambucil were loaded into biodegradable polymeric nanopartides coated with an anti-CD20 antibody.We first demonstrated the ability of the nanoparticles to target and internalize in tumor B-cells. Moreover, these nanoparticles could kill not only p53-mutated]deleted leukemia cells expressing a low amount of CD20, but also circulating primary ceils isolated from chronic lymphocytic leukemia patients. The safety of these nanoparticles was also demonstrated in healthy mice, and their therapeutic effects were shown in a new model of aggressive leukemia. These results showed that anti-CD20 nanoparticles containing hydroxychloroquine and chlorambucil can be effective in controlling aggressive leukemia and provided a rationale for adopting this approach for the treatment of other B-cell disorders.