Resistance to targeted therapy in metastatic colorectal cancer:Current status and new developments

Colorectal cancer(CRC)is one of the most lethal and common malignancies in the world.Chemotherapy has been the conventional treatment for metastatic CRC(mCRC)patients.However,the effects of chemotherapy have been unsatisfactory.With the advent of targeted therapy,the survival of patients with CRC have been prolonged.Over the past 20 years,targeted therapy for CRC has achieved substantial progress.However,targeted therapy has the same challenge of drug resistance as chemotherapy.Consequently,exploring the resistance mechanism and finding strategies to address the resistance to targeted therapy,along with searching for novel effective regimens,is a constant challenge in the mCRC treatment,and it is also a hot research topic.In this review,we focus on the current status on resistance to existing targeted therapies in mCRC and discuss future developments.

Challenges and exploration for immunotherapies targeting cold colorectal cancer

In recent years,immune checkpoint inhibitors(ICIs)have made significant breakthroughs in the treatment of various tumors,greatly improving clinical efficacy.As the fifth most common antitumor treatment strategy for patients with solid tumors after surgery,chemotherapy,radiotherapy and targeted therapy,the therapeutic response to ICIs largely depends on the number and spatial distribution of effector T cells that can effectively identify and kill tumor cells,features that are also important when distinguishing malignant tumors from“cold tumors”or“hot tumors”.At present,only a small proportion of colorectal cancer(CRC)patients with deficient mismatch repair(dMMR)or who are microsatellite instability-high(MSI-H)can benefit from ICI treatments because these patients have the characteristics of a“hot tumor”,with a high tumor mutational burden(TMB)and massive immune cell infiltration,making the tumor more easily recognized by the immune system.In contrast,a majority of CRC patients with proficient MMR(pMMR)or who are microsatellite stable(MSS)have a low TMB,lack immune cell infiltration,and have almost no response to immune monotherapy;thus,these tumors are“cold”.The greatest challenge today is how to improve the immunotherapy response of“cold tumor”patients.With the development of clinical research,immunotherapies combined with other treatment strategies(such as targeted therapy,chemotherapy,and radiotherapy)have now become potentially effective clinical strategies and research hotspots.Therefore,the question of how to promote the transformation of“cold tumors”to“hot tumors”and break through the bottleneck of immunotherapy for cold tumors in CRC patients urgently requires consideration.Only by developing an in-depth understanding of the immunotherapy mechanisms of cold CRCs can we screen out the immunotherapy-dominant groups and explore the most suitable treatment options for individuals to improve therapeutic efficacy.