Although immune checkpoint inhibitors are only entering their adolescence, they are currently proving to be without doubt the most effective therapeutic option available to promote anti-tumor immunity. immunotherapy and immune checkpoints Improvements in malignancy immunotherapy have resulted in amazing success in the treatment of a variety of human cancers. Conceptual developments, such as the understanding that immune responses are routinely generated against tumor-specific neoantigens (derived from proteins mutated in the malignancy) and that these responses are usually limited by immunosuppressive tumor microenvironments, have been key to the development of immunotherapies capable of promoting immunological control of tumor progression. Such therapies can take action either passively, by inhibiting suppressive microenvironment features, or actively, by stimulating anti-tumor immune responses. To date, therapies that block inhibitory immunological signaling pathways (immune checkpoints) promoted within tumor microenvironments have demonstrated the greatest clinical benefit. The posterchild for this success has been the use of (R)-Baclofen monoclonal-antibody-based therapies targeting the PD1 receptor upregulated on activated T cells, or its ligands (programmed death ligands 1 and 2 (PD-L1 and PD-L2)), generally upregulated by tumor and tumor-associated immune cells. By limiting this conversation, anti-PD1/PD-L1 therapy can release T cells (primarily CD8+ T cells) from (or prevent the induction of) a state of functional exhaustion in which effector functions are significantly diminished [1]. Acquired resistance to anti-PD1/PD-L1 immunotherapy Although anti-PD1/PD-L1 therapy is, to date, the most effective single-agent therapy used in the treatment of cancers such as melanoma, (R)-Baclofen it has been shown that as many as 60?% of patients who receive it display primary resistance [2]. More worryingly still, a recent study showed that approximately 25?% of melanoma patients who demonstrated an objective response to anti-PD1 therapy developed acquired resistance, as characterized by disease progression at a median follow-up of 21?months [3]. Unfortunately, few effective therapeutic options are available for such patients, as very little is known regarding the mechanisms by which acquired resistance to anti-PD1/PD-L1 therapy occurs [4]. In a recent edition of or genes were capable of presenting antigen and of being recognized by cognate antigen-specific T (R)-Baclofen cells. Interestingly, however, the sensitivity of the tumor cells to T-cell-derived IFNs was dramatically decreased, evidenced by reduced sensitivity to the anti-proliferative effects of IFNs, decreased signal transducer and activator of transcription 1 (STAT1) phosphorylation (an important transcription factor, phosphorylated by JAK1 and 2), and reduced upregulation of major histocompatibility complex (MHC) class I and PD-L1 in response to IFNs. The second pathway shown to promote resistance to anti-PD1 therapy was a familiar face [5]: a mutation within the gene encoding -2-microglobulin (represent tumor cells and different represent intra-tumor heterogeneity with respect to genetic composition. The harbors T-cell resistance mutations. b Tumor at maximum response. Although the bulk of the tumor is sensitive to immunological assault as a result of anti-PD1 therapy, tumor cells harboring resistance genes are selected for, increasing the ratio of T-cell-resistant to non-resistant cells. c Tumor at progression. The tumor is largely composed of cells containing resistance genes. In the absence of immunological control, metastatic disease is capable of progression and metastasis Primary and acquired resistance to anti-PD1 therapy in other studies This study very effectively demonstrated that like molecularly targeted therapies, immunotherapies can select for tumor cells resistant to pathways normally vulnerable to T-cell-mediated assault in humans. This complements the findings of others who have used mouse models to show that acquired resistance to anti-PD1 therapy can develop by non-genetic means, via upregulation of additional exhaustion markers such as T-cell immunoglobulin mucin 3 (Tim3) Hmox1 [6]; however, it is not clear whether such effects will be observed in human disease. Other studies investigating resistance to anti-PD1 therapy have focused upon primary resistance and have suggested that a number of factors can promote T-cell resistance, such as poor tumor immunogenicity.