“…127 The constitution and organization of spheroids, including hypoxia, altered cellular energy metabolism, the acidic microenvironment, cellular heterogeneity, including the presence of cancer stem cells and cell-cell and cell-ECM interactions, are all thought to contribute to increased resistance to chemotherapeutic drugs. 128 Some research revealed that cells in multicellular tumor spheroids (MCTS) are similarly or even more vulnerable to anticancer drugs than their 2D monolayer counterparts, despite the majority of studies demonstrating that cells in spheroids are more chemoresistant than cells in 2D monolayers. 129 For instance, it was demonstrated that both tumor cells grown in monolayer cell culture and tumor cells grown as multicellular spheroids were susceptible to the proteasome inhibitor PS-341's effects.…”