Can spatially resolved metabolomics uncover weak points in tumors?

The complexity and diversity derived from genetics and evolution lead to tumor heterogeneity. The spatial and temporal evolution of tumor heterogeneity during tumor development results in the dynamic reprogramming of the tumor microenvironment (TME) [1]. Over the last decade, technological developments from bulk genome to single-cell sequencing have provided us with ever-more powerful tool to investigate what happens in TME [2]. Since reprogrammed energy metabolism is one of the hallmarks of cancer, metabolomics may provide a new direction for shedding light on the interactions between small molecules (mainly molecules with molecular weight less than 2000 Da) and other biomolecules in tumors. However, traditional metabolomics cannot give spatiallyrelated information unless combined with spatially resolved sampling, but revealing the metabolic reprogramming characteristics of TME and clarifying the targeting heterogeneity of antitumor drugs rely on the spatial information of metabolites or small molecule drugs. Thus, the advent of spatial metabolomics provides an opportunity to detect molecular localization based on the relative abundance of molecules and to directly correlate changes in small molecules with anatomical features. In other words, spatial metabolomics is oriented to reveal the spatial distribution and variation of metabolites [3]. Most of spatially resolved metabolomics combine ionization techniques with label-free, high-throughput mass spectrometry imaging (MSI) to obtain information on the spatial distribution of metabolites. In addition, laser capture microdissection technique combined with mass spectrometry detection is also one of the research directions in spatial metabolomics, it can select the area of interest for detailed study. Developments in MSI now make it possible to directly observe metabolic changes in tissues, even in single cells. To date, most spatial metabolomics techniques are based on matrix-assisted laser desorption ionization mass spectrometry imaging (MALDI-MSI) or desorption electrospray ionization mass spectrometry imaging (DESI-MSI), both of which are constantly being improved [4]. In recent years, spatially resolved metabolomics has reaped a series of groundbreaking insights in the fields of metabolic heterogeneity of tumors, rapid diagnosis (including tumor boundary determination), metabolic typing, targeting efficiency of antitumor drugs, and efficacy assessment by obtaining information on the distribution of metabolites and smallmolecule drugs in TME (Figure 1). The development of spatially resolved metabolomics technologies will help open the black box of TME and provide new opportunities for precision treatment of tumors.