One of the biggest advances in cancer therapy in the past century has been the recognition that the immune system can be targeted by drugs to trigger immunity against tumors. These drugs, called ‘immunotherapies’ have improved survival for patients in a large and growing number of cancers. However, across cancer types, most patients do not durably benefit from treatment. The reasons for this lack of benefit in particular tumor types and patient populations are unclear. We have developed an approach that leverages new technologies that give us insight into the states and activities of individual tumor and immune cells directly isolated from patient tumors. This approach allows us to dissect mechanisms of resistance to immunotherapy and cellular responses to novel treatments. We are applying our strategy in head and neck cancers, an under‐studied class of tumors that is diagnosed in more than 60,000 people in the US each year. Our preliminary studies have identified distinct immune suppressive pathways enriched in head and neck cancer. In the present project we will test whether drugs aimed at targeting these pathways can restore the anti‐tumor activation of immune cells. If successful, these studies aim to: i) validate the use of novel combination immunotherapies for head and neck cancer and ii) identify biomarkers of response that will allow us to select the patients who will most benefit from these combinations.