Cancer cells adapt to fluctuating microenvironments by rewiring intracellular signaling and protein–protein interaction networks, including through stress-induced epichaperome assemblies that support malignant phenotypes and tumor-associated cells. However, the structural basis of epichaperome formation remains unclear. In this study, we apply a computational systems biology approach, using molecular modeling and dynamics simulations, to define how post-translational modifications (phosphorylation) drive epichaperome assembly of a pentameric  complex (HSP90β(A-B)–HSP70(2)–HOP) by comparing WT (HSP90S226/S255), phosphomimetic (S226E/S255E), and non-phosphorylatable (S226A/S255A) variants. The simulations show that phosphorylation of the HSP90 charged linker promotes β-strand formation and stabilizes inter-protomer contacts, enabling higher-order multimerization consistent with epichaperome structures observed in tumor cells. These results provide a mechanistic framework for how tumors hijack chaperone networks to modulate immune pathways and suggest new strategies to disrupt pathogenic PPI networks and restore anti-tumor immunity.