The tumor microenvironment (TME) plays a crucial role in orchestrating tumor cell behavior and cancer progression. Recent advances in spatial profiling technologies have uncovered novel spatial signatures, including univariate distribution patterns, bivariate spatial relationships, and higher-order structures. These signatures have the potential to revolutionize tumor mechanism and treatment. In this review, we summarize the current state of spatial signature research, highlighting computational methods to uncover spatially relevant biological significance. We discuss the impact of these advances on fundamental cancer biology and translational research, address current challenges and future research directions.