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This work presents a new framework for a competitive evolutionary game between monoclonal antibodies and signalling pathways in oesophageal cancer. The framework is based on a novel dynamical model that takes into account the dynamic progression of signalling pathways, resistance mechanisms and monoclonal antibody therapies. This game involves a scenario in which signalling pathways and monoclonal antibodies are the players competing against each other, where monoclonal antibodies use Brentuximab and Pembrolizumab dosages as strategies to counter the evolutionary resistance strategy implemented by the signalling pathways. Their interactions are described by the dynamical model, which serves as the game’s playground. The analysis and computation of two game-theoretic strategies, Stackelberg and Nash equilibria, are conducted within this framework to ascertain the most favourable outcome for the patient. By comparing Stackelberg equilibria with Nash equilibria, numerical experiments show that the Stackelberg equilibria are superior for treating signalling pathways and are critical for the success of monoclonal antibodies in improving oesophageal cancer patient outcomes.