Recent advances as well as obstacles for immune-based cancer treatment strategies, highlight the notable impact of patient cancer microenvironments on the immune cells and immune targets. Here, we use patient-derived scaffolds (PDS) generated from 110 primary breast cancers to monitor the impact of the cancer microenvironment on immune regulators. Pronounced variation in PD-L1 expression is observed in cancer cells adapted to different patient scaffolds. This variation is further linked to clinical observations and correlated with specific proteins detected in the cell-free PDSs using mass spectrometry. When adding T cells to the PDS-based cancer cultures, the killing efficiency of activated T cells vary between the cultures, whereas non-activated T cells modulate the cancer cell PD-L1 expression to treatment-predictive values, matching killing capacities of activated T cells. Surviving cancer cells show enrichment in cancer stem cell and epithelial-to-mesenchymal transition (EMT) features, suggesting that T cells may not efficiently target cells with metastatic potential. We conclude that clinically relevant insights in how to optimally target and guide immune-based cancer therapies can be obtained by including patient-derived scaffolds and cues from the cancer microenvironment in cancer patient handling and drug development.
© 2025. The Author(s).