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Mantle cell lymphoma (MCL) is a rare and aggressive B-cell non-Hodgkin lymphoma, characterized by specific markers such as cyclin D1 and SOX11, along with a well-defined mutational profile. More recently, studies have highlighted the central role of the tumor microenvironment in disease progression and the development of therapeutic resistance, through complex interactions within protective ecosystems. These major advances in the understanding of MCL biology, combined with optimized clinical protocols, have led to a paradigm shift, with prolonged remissions now achievable in some patients following immunochemotherapy. However, the toxicity of such treatments limits their use in frail patients, and a significant proportion of high-risk, refractory cases still lack effective therapeutic options. In this context, the rapid emergence of targeted therapies and immunotherapeutic approaches offers new perspectives by counteracting malignant plasticity and intratumoral heterogeneity. This review first provides an overview of current standards in MCL management, then explores how both intrinsic tumor alterations and interactions with the microenvironment contribute to resistance mechanisms. We then present recent strategies aimed at targeting tumor vulnerabilities within its protective niches. Finally, we discuss the potential of emerging approaches — such as the modulation of epigenetic dysregulation and the restoration of functional lymphoid immunity through modern immunotherapies — as a foundation for future therapeutic options for patients currently facing treatment failure.