The right Timing, right combination, right sequence, and right delivery for Cancer immunotherapy

Cancer immunotherapy (CI) represented by immune checkpoint inhibitors (ICIs) presents a new paradigm for cancer treatment. However, the types of cancer that attain a therapeutic benefit from ICIs are limited, and the efficacy of these treatments does not meet expectations. To date, research on ICIs has mainly focused on identifying biomarkers and patient characteristics that can enhance the therapeutic effect on tumors. However, studies on combinational strategies for CI are being actively conducted to overcome the resistance to ICI treatment. Moreover, it has been confirmed that dramatic anticancer effects are achieved through "neoadjuvant" immunotherapy with ICIs in treatment-naïve cancer patients; consequently, it has become necessary to consider how to best apply cancer immunotherapies for patients, even with respect to their tumor stages. In this review, we sought to discuss the right timing of ICI treatment in consideration of the progression of cancer with a changing tumor-immune microenvironment. Furthermore, we investigated which types of combinational treatments and their corresponding sequences of administration could optimize the therapeutic effect of ICIs to expand the applicable target of ICIs and increase their therapeutic efficacy. Finally, we discussed several delivery pathways and methods that can maximize the effect of ICIs.