Figure 6. Schematic summary of the proposed model of T-DM1 sensitivity, resistance and targeting T-DM1 resistance.

A In T-DM1 sensitive tumors, the activation of spindle assembly checkpoint (SAC) and mitotic arrest lead to apoptosis and activation of ICD markers, e.g., eIF2α phosphorylation, ATP secretion, calreticulin surface exposure, and HMGB1 release, leading to DC maturation and cytotoxic T cell, culminating in tumor growth inhibition. B In T-DM1 resistant tumors, overexpression of TACC3 prevents activation of SAC, mitotic cell death and ICD, thus promoting cell survival. C Inhibition of TACC3 in combination with T-DM1 in the resistant tumors restores SAC activation and mitotic arrest, leading to apoptosis and ICD induction, thereby increasing the infiltration of DCs and T cells, thus restoring T-DM1 sensitivity. This figure was drawn using Biorender.com.