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Over the last decade, the cell-cycle inhibitor p21 has been shown to sustain leukaemia propagation with two distinct mechanisms. On one hand, p21 was shown to be critical for maintaining increased self-renewal capacities of leukaemia stem cells. Indeed, the absence of p21 in leukaemia stem cells leads to their functional exhaustion, which results in loss of leukaemia transplantability in syngeneic mice. On the other hand, p21 expression is crucial for evading the surveillance mechanisms of the immune system, thus ensuring tumor growth. Specifically, lack of p21 in the leukemic microenvironment activates a potent CD4+ T-cell mediated immunological response against tumor in syngeneic context (un-published data from the host laboratory). To translate the observed p21-dependent anti-tumoral immunity into novel immune-therapies against cancer, underlying mechanisms needed to be unrevealed. In my thesis work, I dissected the cellular bases of the p21-dependent anti-tumor immuni-ty. I disclosed a crucial role of the p21-/- tumor microenvironment in triggering activation of an anti-tumor immunological response. In particular, for the first time I identified rare iron-loaded CD68+ tumor-associated macrophages (iTAMs) in the p21-null context as key me-diators of a potent immunological mechanisms of cancer clearance. By unravelling crucial players of the p21-dependent anti-tumor immunity, my work set the basis for the future de-sign of novel anti-cancer vaccines. Such vaccines will grant more efficient and less toxic treatment for cancer patients. To further transpose such immunological mechanism of cancer clearance in humans, the us-age of a proper humanized mouse model is needed. Actually, humanized mice allow to study the interaction between human immune system and cancers of human origin. I gener-ated hCB-CD34+ NSG mice containing all the cellular components of human immunity. However, I showed that these mice are fully accessible to human tumor growth, demon-strating the inadequacy of hCB-CD34+ NSG model in immuno-oncology. Thus, the devel-opment of a proper humanized mouse model to study p21-dependent anti-tumoral immune response in human context remains necessary.