Mutation in p53 is the most frequent event in cancer development and a leading cause of cancer therapy resistance due to evasion of the apoptosis cascade. Beyond chemotherapies and radiation therapies, growing evidence indicates that p53-mutant tumors are resistant to a broad range of immune-based therapies, such as immune checkpoint inhibitors, chimeric antigen receptor (CAR) T, and hematopoietic stem cell transplantation (HSCT). This highlights the role of p53 mutations in driving immune evasion of tumor cells. In this review, we first summarize recent studies revealing mechanisms by which p53-mutant tumors evade immune surveillance from T cells, natural killer (NK) cells, and macrophages. We then review how these mutant tumor cells reshape the tumor microenvironment (TME), modulating bystander cells such as macrophages, neutrophils, and regulatory T (Treg) cells to foster immunosuppression. Additionally, we review clinical observations indicative of immune evasion associated with p53 loss or mutations. Finally, we discuss therapeutic strategies to enhance immune response in p53 wild-type (WT) or mutant tumors.

PPM1D encodes a phosphatase that is recurrently activated across cancer, most notably in therapy-related myeloid neoplasms. However, the function of PPM1D in hematopoiesis and its contribution to tumor cell growth remain incompletely understood. Using conditional mouse models, we uncover a central role for Ppm1d in hematopoiesis and validate its potential as a therapeutic target. We find that Ppm1d regulates the competitive fitness and self-renewal of hematopoietic stem cells (HSCs) with and without exogenous genotoxic stresses. We also show that although Ppm1d activation confers cellular resistance to cytotoxic therapy, it does so to a lesser degree than p53 loss, informing the clonal competition phenotypes often observed in human studies. Notably, loss of Ppm1d sensitizes leukemias to cytotoxic therapies in vitro and in vivo, even in the absence of a Ppm1d mutation. Vulnerability to PPM1D inhibition is observed across many cancer types and dependent on p53 activity. Importantly, organism-wide loss of Ppm1d in adult mice is well tolerated, supporting the tolerability of pharmacologically targeting PPM1D. Our data link PPM1D gain-of-function mutations to the clonal expansion of HSCs, inform human genetic observations, and support the therapeutic targeting of PPM1D in cancer.

In many cancers, mortality is associated with the emergence of relapse with multidrug resistance (MDR). Thus far, the investigation of cancer relapse mechanisms has largely focused on acquired genetic mutations. Using acute myeloid leukemia (AML) patient-derived xenografts (PDX), we systematically elucidated a basis of MDR and identified drug sensitivity in relapsed AML. We derived pharmacologic sensitivity for 22 AML PDX models using dynamic BH3 profiling (DBP), together with genomics and transcriptomics. Using in vivo acquired resistant PDXs, we found that resistance to unrelated, narrowly targeted agents in distinct PDXs was accompanied by broad resistance to drugs with disparate mechanisms. Moreover, baseline mitochondrial apoptotic priming was consistently reduced regardless of the class of drug-inducing selection. By applying DBP, we identified drugs showing effective in vivo activity in resistant models. This study implies evasion of apoptosis drives drug resistance and demonstrates the feasibility of the DBP approach to identify active drugs for patients with relapsed AML. Significance: Acquired resistance to targeted therapy remains challenging in AML. We found that reduction in mitochondrial priming and common transcriptomic signatures was a conserved mechanism of acquired resistance across different drug classes in vivo. Drugs active in vivo can be identified even in the multidrug resistant state by DBP.

The tumor microenvironment (TME) programs cancer cells to influence therapeutic responses. Macrophages residing in TME switch from pro-phagocytic to tumor-promoting and immunosuppressive phenotypes as cancer develops. While these pro-tumor functions of macrophages are associated with poor outcomes, the underlying mechanisms by which bone-marrow (BM)-associated macrophages fuel myeloid malignancy and their precise contribution to relapse remain undissected. Here, we show expansion of monocyte/macrophage population in leukemia patients post-chemotherapy relapse, and spatial proximity of macrophages to leukemia blasts in the BM niche. This proximity proved functionally consequential—depletion of macrophages delayed leukemia relapse post cytarabine (AraC), a frontline chemotherapy, in patient-derived xenografts (PDX) and syngeneic leukemia models. Mechanistically, a pyrimidine metabolite, deoxycytidine (dC), secreted by BM macrophages, is taken up by leukemia cells to directly inhibit deoxycytidine kinase (DCK) to hamper AraC activation and subsequent resistance in a cell non-autonomous manner. Diagnosis AML patients exhibited significantly higher circulating dC levels than healthy donors, and dC levels further increased following chemotherapy. SAMHD1, which catalyzes deoxynucleoside triphosphates (dNTPs) into deoxynucleoside, was highly abundant in macrophages and mediated dC accumulation. Blockade of dC production in mouse and human macrophages via genetic and pharmacological inhibition of SAMHD1 or DHODH , a critical enzyme in pyrimidine synthesis, restored AraC sensitivity. Combination with DHODH inhibitors significantly delayed AraC relapse in human PDX and mouse syngeneic AML models. Collectively, we identify a metabolic immune–leukemia crosstalk in which SAMHD1 ^high macrophages mediates chemoresistance by secreting pyrimidine metabolites and propose macrophage metabolic reprogramming as a tractable strategy to overcome TME-driven chemoresistance in myeloid leukemia.

Supplemental table legends 1-4.

Supplemental Figure 8 shows ex vivo DBP profiling in AML PDX models guides generation of drug-resistant PDXs.