After decades of intense effort, immune checkpoint inhibitors have been conclusively demonstrated to be effective in cancer treatments and thus are revolutionizing the concepts in the treatment of cancers. Immuno-oncology has arrived and will play a key role in cancer treatment in the foreseeable future. However, efforts to find novel methods to improve the immune response to cancer have not ceased. Small-molecule approaches offer inherent advantages over biologic immunotherapies since they can cross cell membranes, penetrate into tumor tissue and tumor microenvironment more easily, and are amenable to be finely controlled than biological agents, which may help reduce immune-related adverse events seen with biologic therapies and provide more flexibility for the combination use with other therapies and superior clinical benefit. On the one hand, small-molecule therapies can modulate the immune response to cancer by restoring the antitumor immunity, promoting more effective cytotoxic lymphocyte responses, and regulating tumor microenvironment, either directly or epigenetically. On the other hand, the combination of different mechanisms of small molecules with antibodies and other biologics demonstrated admirable synergistic effect in clinical settings for cancer treatment and may expand antibodies' usefulness for broader clinical applications. This chapter provides an overview of small-molecule immunotherapeutic approaches either as monotherapy or in combination for the treatment of cancer.
Keywords: Cancer immunotherapy; Combination therapy; Cytotoxic lymphocyte responses; Drug screening; Small molecules.