During tumor evolution, cancer cells use the tumor-stroma crosstalk to reorganize the microenvironment for maximum robustness of the tumor. The success of immune checkpoint therapy foretells a new cancer therapy paradigm: an effective cancer treatment should not aim to influence the individual components of super complex intracellular interactomes (molecular targeting), but try to disrupt the intercellular interactions between cancer and stromal cells, thus breaking the tumor as a whole. Arguments are provided in favor of a hypothesis that such interactions include formation of synapse-like structures (interfaces) where the interacting cells are located at a distance of ∼10–15 nm. Within these interfaces, molecules initiating and strengthening the interaction are organized, and allow optimum cross-signaling; a very confined intercellular space facilitates the concentration of secreted cytokines, enhancing the paracrine cross-communication. These features of tumors form a druggable cancer hallmark the tumor-stroma symbiotic crosstalk—which represents a new target for efficient cancer drug discovery.