1. SIMS-based methods. SIMS, originally demonstrated by Herzog and Biehböck in 1949 , evolved for single-cell analysis in the 1960s . SIMS provides sensitive analysis of surface compositions by sputtering analytes with a focused primary ion beam (e.g., O⁻, O₂⁺, and Ar⁺), which generates secondary ions from surface molecules. The established SIMS methods for single-cell analysis include TOF-SIMS , nanoSIMS , and the newer GCIB-SIMS . These techniques render high spatial resolution (e.g., 50 nm spatial resolution can be achieved using nanoSIMS); however, challenges remain for analyzing small biological samples like single cells . These challenges include the high vacuum requirement, low ionization efficiency for biomolecules, and complex data analysis due to extensive fragmentation from high-energy ion bombardment . Advances in the ion beam source, such as the GCIB, have been introduced to mitigate fragmentation .