Background With the recent advances in the understanding of the interaction of the immune system with developing tumor, it has become imperative to consider the immunological parameters for both cancer diagnosis and disease prognosis. Additionally, in the era of emerging immunotherapeutic strategies in cancer, it is very important to follow the treatment outcome and also to predict the correct immunotherapeutic strategy in individual patients. There being enormous heterogeneity among tumors at different sites or between primary and metastatic tumors in the same individual, or interpatient heterogeneity, it is very important to study the tumor‐immune interaction in the tumor microenvironment and beyond. Importantly, molecular tools and markers identified for such studies must be suitable for monitoring in a noninvasive manner. Recent findings Recent studies have shown that the immune checkpoint molecules play a key role in the development and progression of tumors. In‐depth studies of these molecules have led to the development of most of the cancer immunotherapeutic reagents that are currently either in clinical use or under different phases of clinical trials. Interestingly, many of these cell surface molecules undergo alternative splicing to produce soluble isoforms, which can be tracked in the serum of patients. Conclusions Several studies demonstrate that the serum levels of these soluble isoforms could be used as noninvasive markers for cancer diagnosis and disease prognosis or to predict patient response to specific therapeutic strategies.