The multi-region integrated energy system (MRIES) is one promising option for exploiting the complementarity potentials between power system, thermal system and loads, as well as improving flexibility and economic competitiveness. However, the optimal planning has remained challenging since it involves multiple forms of energies with the nature of coupling. A mixed integer linear programming (MILP) model is proposed for joint optimization of MRIES planning and operation, which considers the flexible load’s demand response (DR). It is realized by combining the multi-region heating network IES coupling model with the flexible cooling-heating-electric load DR model. The results show that the proposed model can assist planners to comprehensively analyze and evaluate the impacts of multiple factors on planning, and to determine the optimal planning configuration and operation strategy.