Molecular Mechanisms and Countermeasures of Immunotherapy Resistance in Malignant Tumor

Tumor immunotherapy inhibits the proliferation and invasion of tumor cells by inducing or enhancing anti-tumor immune responses in active or passive ways. It is the fourth therapeutic method with efficiency and safety in addition to surgery, radiotherapy and chemotherapy. At present, anti-tumor immune related clinical trials have made promising achievements in prolonging progression free survival and overall survival, therefore, FDA approved a variety of immune checkpoint blockers (ICBs) such as nivolumab, pembrolizumab, ipilimumab. However, primary or acquired resistance results in massive perplexity to oncologist and patients. In order to bring further clinical benefit to tumor patients, study on mechanisms of immunotherapy resistance is extremely urgent. This review summarizes related mechanisms of tumor immunotherapy resistance, including MITF suppression, Ezh2 upregulation, TIM-3 upregulation, microRNA-driven deregulation of cytokine expression and et al. Genetic mutations such as PTEN loss, JAK1/2 loss-of-function mutations and Cbl-b deficiency are also involved. Moreover, we have discussed feasible countermeasures, for instance, combining ICBs with PRRs agonists, ARNAX, CpG oligonucleotide, oncolytic peptide LTX-315 and indoleamine 2, 3-dioxygenase inhibitors, respectively. Other methods include combined ICBs with radiotherapy, combined ICBs with blockade of PI3K-AKT, TIM-3 pathway; blockade of Fcγ receptors before anti-PD-1 monoclonal antibodies administration and modulation of the gut microbiome, et al. Mechanisms and countermeasures of immunotherapy resistance still requires further exploration, in expectation to provide novel ideals and basis for tolerant patients.