The protein phosphatase SHP2/PTPN11 has been reported to be a key modulator of proliferative pathways in a wide range of malignancies. Intriguingly, SHP2 has also been described as a critical regulator of the tumor microenvironment. Based on this evidence SHP2 is considered a multifaceted target in cancer, spurring the notion that the development of direct inhibitors of SHP2 would provide the twofold benefit of tumor intrinsic and extrinsic inhibition. In this review, we will discuss the role of SHP2 in cancer and the tumor microenvironment, and the clinical strategies in which SHP2 inhibitors are leveraged as combination agents to improve therapeutic response. SIGNIFICANCE: The SHP2 phosphatase functions as a pleiotropic factor, and its inhibition not only hinders tumor growth but also reshapes the tumor microenvironment. Although their single-agent activity may be limited, SHP2 inhibitors hold the potential of being key combination agents to enhance the depth and the durability of tumor response to therapy.

The BCL2 inhibitor venetoclax has recently emerged as an important component of acute myeloid leukemia (AML) therapy. Notably, use of this agent has revealed a previously unrecognized form of pathogenesis characterized by monocytic disease progression. We demonstrate that this form of disease arises from a fundamentally different type of leukemia stem cell (LSC), which we designate as monocytic LSC (m-LSC), that is developmentally and clinically distinct from the more well-described primitive LSC (p-LSC). The m-LSC is distinguished by a unique immunophenotype (CD34-, CD4+, CD11b-, CD14-, CD36-), unique transcriptional state, reliance on purine metabolism, and selective sensitivity to cladribine. Critically, in some instances, m-LSC and p-LSC subtypes can co-reside in the same patient with AML and simultaneously contribute to overall tumor biology. Thus, our findings demonstrate that LSC heterogeneity has direct clinical significance and highlight the need to distinguish and target m-LSCs as a means to improve clinical outcomes with venetoclax-based regimens. SIGNIFICANCE: These studies identify and characterize a new type of human acute myeloid LSC that is responsible for monocytic disease progression in patients with AML treated with venetoclax-based regimens. Our studies describe the phenotype, molecular properties, and drug sensitivities of this unique LSC subclass. This article is featured in Selected Articles from This Issue, p. 1949.

Cancer is an age-related disease, with the majority of patients receiving their diagnosis after the age of 60 and most mortality from cancer occurring after this age. The tumor microenvironment changes drastically with age, which in turn affects cancer progression and treatment efficacy. Age-related changes to individual components of the microenvironment have received well-deserved attention over the past few decades, but the effects of aging at the interface of two or more microenvironmental components have been vastly understudied. In this perspective, we discuss the relationship between the aging extracellular matrix and the aging immune system, how they affect the tumor microenvironment, and how these multidisciplinary studies may open avenues for new therapeutics. Cancer is a disease of aging. With a rapidly aging population, we need to better understand the age-related changes that drive tumor progression, ranging from secreted changes to biophysical and immune changes.

Cancer health disparities are complex and a mixture of factors that need to be accounted for in both our planning, implementation, and execution across all researchers, especially in single-cell and spatial technologies, which have a higher burden for adoption in low- and middle-income countries. This commentary tackles the hurdles these technologies face in creating a diverse, representative atlas of cancer and is a call to arms for a strategic plan toward inclusivity across all global populations.

Fumarate accumulation due to loss of fumarate hydratase (FH) drives cellular transformation. Germline FH alterations lead to hereditary leiomyomatosis and renal cell cancer (HLRCC) where patients are predisposed to an aggressive form of kidney cancer. There is an unmet need to classify FH variants by cancer-associated risk. We quantified catalytic efficiencies of 74 variants of uncertain significance. Over half were enzymatically inactive, which is strong evidence of pathogenicity. We next generated a panel of HLRCC cell lines expressing FH variants with a range of catalytic activities, then correlated fumarate levels with metabolic features. We found that fumarate accumulation blocks de novo purine biosynthesis, rendering FH-deficient cells reliant on purine salvage for proliferation. Genetic or pharmacologic inhibition of the purine salvage pathway reduced HLRCC tumor growth in vivo. These findings suggest the pathogenicity of patient-associated FH variants and reveal purine salvage as a targetable vulnerability in FH-deficient tumors. SIGNIFICANCE: This study functionally characterizes patient-associated FH variants with unknown significance for pathogenicity. This study also reveals nucleotide salvage pathways as a targetable feature of FH-deficient cancers, which are shown to be sensitive to the purine salvage pathway inhibitor 6-mercaptopurine. This presents a new rapidly translatable treatment strategy for FH-deficient cancers. This article is featured in Selected Articles from This Issue, p. 1949.

The introduction of immunotherapy has ushered in a new era of anticancer therapy for many cancer types including melanoma. Given the increasing development of novel compounds and combinations and the investigation in earlier disease stages, the need grows for biomarker-based treatment personalization. Stage III melanoma is one of the front-runners in the neoadjuvant immunotherapy field, facilitating quick biomarker identification by its immunogenic capacity, homogeneous patient population, and reliable efficacy readout. In this review, we discuss potential biomarkers for response prediction to neoadjuvant immunotherapy, and how the neoadjuvant melanoma platform could pave the way for biomarker identification in other tumor types. SIGNIFICANCE: In accordance with the increasing rate of therapy development, the need for biomarker-driven personalized treatments grows. The current landscape of neoadjuvant treatment and biomarker development in stage III melanoma can function as a poster child for these personalized treatments in other tumors, assisting in the development of new biomarker-based neoadjuvant trials. This will contribute to personalized benefit-risk predictions to identify the most beneficial treatment for each patient.