LA-ICP-TOFMS Imaging Reveals Significant Influence of Cancer Cell Resistance on Oxaliplatin Compartmentalization in the Tumor Microenvironment

Chemoresistance in cancer cells, particularly in refractory types, such as colorectal cancer, poses a major challenge to effective treatment. In particular, the interaction between cancer cells and the tumor microenvironment (TME) has been shown to exert substantial influence on the efficacy of therapeutic agents. This study investigated whether an intrinsic resistance phenotype alters drug distribution in the TME using xenograft models derived from HCT116 colorectal cancer cells, including oxaliplatin (OxPt)-sensitive and OxPt-resistant (OxR) variants. Tumors were prepared as formalin-fixed paraffin-embedded (FFPE) sections, followed by single-cell analysis with laser ablation inductively coupled plasma time-of-flight mass spectrometry (LA-ICP-TOFMS). Based on histological evaluations, a panel of metal-conjugated antibodies was designed to target tissue architecture and distinct cell states within the TME. A dedicated calibration strategy was applied to accurately measure platinum (Pt) uptake in phenotypically defined single cells across both the tumor and its microenvironment. The results revealed substantial structural differences: HCT116/OxR tumors exhibited robust growth following drug administration, while parental tumors displayed extensive degradation. Notably, OxPt accumulated significantly in necrotic regions specific to HCT116/OxR, indicating resistance-dependent changes in drug compartmentalization. These findings suggest that an intrinsically resistant cancer cell phenotype is capable of markedly altering metal distributions within the TME.