纳米材料用于调控癌症免疫应答

Nanomaterials for regulating cancer immune responses

近年来,癌症免疫疗法在临床上取得了巨大的成功并成为癌症治疗的潜在支柱性疗法.然而,以免疫检查点抑制剂和嵌合抗原受体T细胞疗法为代表的肿瘤免疫疗法在临床治疗中却常伴随响应率低、持续时间短、易复发等问题.了解造成免疫疗法局限性的原因对于提高免疫疗法临床疗效至关重要.本文对肿瘤的免疫逃逸通路进行了分析,并归纳了近年来纳米材料在调控癌症免疫应答方面的研究进展,最后总结了当前纳米材料用于癌症免疫疗法中仍存在的问题并提出了克服这些限制的策略.

Cancer immunotherapy is profoundly changing the paradigm in cancer treatment.By regulating the immune system rather than tumor itself,immunotherapy can precisely detect and destroy tumor cells in an antigen-specific manner.In the past few decades,cancer immunotherapies based on chimeric antigen receptor T cells and immune checkpoint inhibitors have shown great potentials in the treatment of various types of cancers.However,the clinical application of cancer immunotherapies still faces challenges,including low response rate and high relapse rate.The immunosuppressive tumor microenvironment(TME)and undesired in vivo distributions are the two major challenges to achieve effective cancer immunotherapy.In TME,the proliferation,infiltration and anti-tumor functions of cytotoxic T cells are inhibited due to the widespread existence of immunosuppressive cells and immunosuppressive chemokines and cytokines.In addition,almost all the antibodies in current cancer immunotherapy are administrated systemically,leading to the low bioavailability of these antibodies due to the poor control of their distribution in vivo.Furthermore,the undesired distribution of the antibodies may cause serious immune-related adverse events.Therefore,there is an urgent need for feasible strategies that can improve the safety and clinical efficacy of cancer immunotherapy.Fortunately,the rapid development of nanotechnology provides more possibilities for safe and efficient cancer immunotherapy.Due to the good biocompatibility and stability,nanomaterials are often used as carriers to improve the biodistribution and pharmacokinetics of probes,therapeutic agents,antibodies and biological ligands.Furthermore,nanomaterials can be engineered to achieve efficient accumulation in tumor tissues to improve therapeutic efficacy as well as reduce side effects.Currently,nanomaterial-based cancer immunotherapies were mainly achieved by delivering therapeutic agents to target.With these strategies,nanomaterial-based cancer immunotherapy has achieved to reduce the effective dosage of therapeutic agents,improve the anti-tumor efficacy and reduce immune-related severe adverse effect,implying the potential of nanomaterials as a feasible platform for the development of advanced cancer immunotherapy.In this review,we first summarized the common immune escape pathways of tumors,including(1)down-regulation of the expression of antigens and costimulatory molecules of cancer cells to avoid the recognition and elimination by effector T cells,(2)over-expression of immunosuppressive factors to inhibit T cells infiltrations,proliferations and its anti-tumor activities,and(3)secretion of apoptosis-related ligands to induce T cell apoptosis.Subsequentially,recent research progress of nanomaterials in regulating cancer immune responses were also discussed in this review.According to different ways to regulate tumor immunity,current nanomaterial-based cancer immunotherapy can be divided into two categories,including nanomaterials that deliver therapeutic agents to modulate immunosuppressive TME,and nanomaterials that deliver therapeutic agents to enhance anti-tumor immunity.To regulate TME,nanomaterial-based immunotherapy achieves tumor suppression by(1)delivering inhibitors that target immunosuppressive factors in TME,(2)delivering immunomodulators to eliminate immunosuppressive immune cells or repolarize pro-inflammatory immune cells into antiinflammatory subtypes,and(3)delivering genetic editing system or antibodies to block immune checkpoints to restore the activity of immune effectors.To enhance the anti-tumor immunity,nanomaterial-based immunotherapy involves(1)delivering cancer vaccine,agonist or immunogenic cell death inducers to enhance tumor immunogenicity,(2)delivering antigen to immune organs to promote antigen presentation,and(3)delivering immunomodulating nanoparticle to in situ activate tumor infiltration effector cells.Finally,challenges and opportunities were discussed for future development of nanomaterial-based cancer immunotherapy.