<p>The immunological synapse, a highly organized cell–cell junction, is an important fulcrum for effective T-cell-mediated killing of cancer cells. In multiple myeloma, however, therapeutic resistance reflects multiple interacting layers, including synaptic disruption, clonal evolution, metabolic reprogramming, and spatially heterogeneous bone-marrow niches, all of which can contribute to T-cell dysfunction and immune escape. This review examines the immunological synapse as a potentially modifiable intercellular interface: we describe how the bone marrow niche impairs synaptic function and summarize strategies that may help restore synaptic structure and signaling. We explore how the myeloma niche deranges synaptic function and then detail innovative strategies to restore its fidelity. We analyze how BiTEs establish synaptic contacts and how CAR-T cells assemble modified synaptic interfaces that have distinct structural and signaling properties; we then compare shared and divergent mechanisms of action. Looking forward, we discuss next-generation approaches, including trispecific antibodies, armored/logic-gated CAR-Ts, niche-modifying agents, and synaptic nanotechnology, which aim to create specific, resilient, and context-aware cytolytic junctions. By framing therapeutic progress through the lens of synaptic engineering, this narrative review selectively integrates mechanistic, translational, and clinical reports supporting synapse-directed interventions, while explicitly separating preclinical models from early-phase and randomized clinical evidence so that hypothesis-generating findings are not treated as equivalent to patient outcome data.</p>