Managing the immune microenvironment of osteosarcoma:the outlook for osteosarcoma treatment

Osteosarcoma,with poor survival after metastasis,is considered the most common primary bone cancer in adolescents.Notwithstanding the efforts of researchers,its five-year survival rate has only shown limited improvement,suggesting that existing therapeutic strategies are insufficient to meet clinical needs.Notably,immunotherapy has shown certain advantages over traditional tumor treatments in inhibiting metastasis.Therefore,managing the immune microenvironment in osteosarcoma can provide novel and valuable insight into the multifaceted mechanisms underlying the heterogeneity and progression of the disease.Additionally,given the advances in nanomedicine,there exist many advanced nanoplatforms for enhanced osteosarcoma immunotherapy with satisfactory physiochemical characteristics.Here,we review the classification,characteristics,and functions of the key components of the immune microenvironment in osteosarcoma.This review also emphasizes the application,progress,and prospects of osteosarcoma immunotherapy and discusses several nanomedicine-based options to enhance the efficiency of osteosarcoma treatment.Furthermore,we examine the disadvantages of standard treatments and present future perspectives for osteosarcoma immunotherapy.

Emerging role of tumor cell plasticity in modifying therapeutic response

Resistance to cancer therapy is a major barrier to cancer management.Conventional views have proposed that acquisition of resistance may result from genetic mutations.However,accumulating evidence implicates a key role of non-mutational resistance mechanisms underlying drug tolerance,the latter of which is the focus that will be discussed here.Such non-mutational processes are largely driven by tumor cell plasticity,which renders tumor cells insusceptible to the drug-targeted pathway,thereby facilitating the tumor cell survival and growth.The concept of tumor cell plasticity highlights the significance of re-activation of developmental programs that are closely correlated with epithelial–mesenchymal transition,acquisition properties of cancer stem cells,and transdifferentiation potential during drug exposure.From observations in various cancers,this concept provides an opportunity for investigating the nature of anticancer drug resistance.Over the years,our understanding of the emerging role of phenotype switching in modifying therapeutic response has considerably increased.This expanded knowledge of tumor cell plasticity contributes to developing novel therapeutic strategies or combination therapy regimens using available anticancer drugs,which are likely to improve patient outcomes in clinical practice.

Overcoming cancer therapeutic bottleneck by drug repurposing

Ever present hurdles for the discovery of new drugs for cancer therapy have necessitated the development of the alternative strategy of drug repurposing,the development of old drugs for new therapeutic purposes.This strategy with a cost-effective way offers a rare opportunity for the treatment of human neoplastic disease,facilitating rapid clinical translation.With an increased understanding of the hallmarks of cancer and the development of various data-driven approaches,drug repurposing further promotes the holistic productivity of drug discovery and reasonably focuses on target-defined antineoplastic compounds.The“treasure trove”of non-oncology drugs should not be ignored since they could target not only known but also hitherto unknown vulnerabilities of cancer.Indeed,different from targeted drugs,these old generic drugs,usually used in a multi-target strategy may bring benefit to patients.In this review,aiming to demonstrate the full potential of drug repurposing,we present various promising repurposed non-oncology drugs for clinical cancer management and classify these candidates into their proposed administration for either mono-or drug combination therapy.We also summarize approaches used for drug repurposing and discuss the main barriers to its uptake.