Immunotherapy by immune checkpoint inhibitors has emerged as an effective treatment for a slight proportion of patients with aggressive tumors. Currently, some molecular determinants, such as the expression of the programmed cell death ligand-1 (PD-L1) or the tumor mutational burden (TMB) have been used in the clinical practice as predictive biomarkers, although they fail in consistency, applicability, or reliability to precisely identify the responding patients mainly because of their spatial intratumoral heterogeneity. Therefore, new biomarkers for early prediction of patient response to immunotherapy, that could integrate several approaches, are eagerly sought. Novel methods of quantitative image analysis (such as radiomics or pathomics) might offer a comprehensive approach providing spatial and temporal information from macroscopic imaging features potentially predictive of underlying molecular drivers, tumor-immune microenvironment, tumor-related prognosis, and clinical outcome (in terms of response or toxicity) following immunotherapy. Preliminary results from radiomics and pathomics analysis have demonstrated their ability to correlate image features with PD-L1 tumor expression, high CD3 cell infiltration or CD8 cell expression, or to produce an image signature concordant with gene expression. Furthermore, the predictive power of radiomics and pathomics can be improved by combining information from other modalities, such as blood values or molecular features, leading to increase the accuracy of these models. Thus, “digital biopsy,” which could be defined by non-invasive and non-consuming digital techniques provided by radiomics and pathomics, may have the potential to allow for personalized approach for cancer patients treated with immunotherapy.