Preleukemia, historically a morphological and cytogenetic diagnosis, is now understood as a continuous clonal process in which somatic mutations, environmental influences, and stem cell pool dynamics interact over decades. Clonal hematopoiesis, the expansion of blood cells carrying somatic mutations, is near-universal in adults over age 70 and confers elevated risk of hematological malignancy, while also acting as a risk factor for cardiovascular and other age-related diseases. Here, we review the genetic and environmental factors that predispose to clonal expansion, organize the mechanisms of clonal expansion into three overlapping and interacting mechanisms (cell-autonomous fitness gain, context-conditional fitness, and nongenetic heritable states), and trace the trajectories that lead from clonal expansion to specific myeloid and lymphoid malignancies. We also discuss methods that have enabled mapping of clonal architecture in human tissue and close on the key questions that we anticipate will define the next decade of research in this field.
Immune privilege, or the capacity of specific tissues to actively limit immune responses, cannot be reduced to passive exclusion. The brain, eye, testis, and placenta each maintain this state through specialized physical barriers, resident immunosuppressive cell populations, and suppression of antigen presentation. Tumor cells metastasizing to these organs co-opt the same molecular programs that immune-privileged tissues evolved to protect themselves, turning biological safeguards into metastatic sanctuaries. The pattern points to selection rather than chance: The cells that thrive are those able to evade specialized immune programs and breach site-specific barriers. Advances in single-cell and spatial profiling, liquid biopsy, and preclinical modeling have now provided the tools to interrogate these ecosystems with previously unavailable resolution. Here, we review the biology of immune-privileged metastatic niches, advances in their detection and molecular profiling, and the therapeutic strategies emerging from this understanding, with an emphasis on molecularly guided treatment over tissue-of-origin classification.
Cellular plasticity, a hallmark of normal development, is frequently co-opted by cancers to drive heterogeneity, metastasis, and therapy resistance. Deciphering these dynamic processes requires lineage-tracing technologies capable of recording cellular ancestry. This review outlines the methodological evolution from widely used site-specific recombinase tools to high-resolution, single-cell DNA barcoding. The integration of lineage tracing with single-cell multiomics and spatial transcriptomics now enables the construction of dynamic atlases that link cellular history to molecular state and microenvironment. Key insights reshaping cancer biology include the frequent polyclonal origin of early lesions followed by Darwinian selection toward monoclonal dominance, the revelation that cancer stem cells represent dynamic and plastic states rather than fixed entities, and the identification of specific cellular states critical for metastasis. This synergistic framework provides a powerful means to delineate the rules of tumor evolution, opening new avenues for predicting cell fates and designing strategies to target the roots of malignancy.
Innate T cells, including invariant natural killer T (iNKT) cells, mucosal-associated invariant T (MAIT) cells, and γδ T cells, bridge innate and adaptive immunity through rapid responses to nonpeptide antigens, metabolites, and stress-associated signals. In cancer, these populations can promote tumor surveillance through cytotoxicity, type 1 cytokine production, tissue-resident immune monitoring, and activation of broader antitumor networks. However, their functions are highly context dependent. Within suppressive tumor microenvironments, tumor-infiltrating unconventional T cell compartments may contain developmentally programmed innate-like subsets together with recruited or locally differentiated cells displaying dysfunctional, regulatory, or IL-17-associated features that support myeloid cell recruitment, chronic inflammation, immune evasion, and therapy resistance. This review discusses the major recognition pathways, functional states, microbiota- and metabolite-dependent regulation, and therapeutic targeting of iNKT, MAIT, and γδ T cells in cancer. We further highlight emerging strategies to harness these cells through endogenous activation, combination immunotherapy, and engineered cell platforms while limiting tumor-promoting inflammatory programs and treatment-associated toxicity.
Metabolic reprogramming supports cancer behaviors including proliferation, survival, and therapeutic resistance. Compared to our understanding of these processes, little is known about the detoxification liabilities that are introduced as a byproduct of this reprogramming. Here, we review recent findings that collectively support the notion that the metabolic reprogramming of cancer cells is accompanied by increased production of potentially toxic metabolites. As a result, these cells are critically dependent on enzymatic processing or export of these metabolites. When such processes are blocked, endogenously produced metabolites can accumulate in distinct subcellular compartments to exert a variety of cytotoxic mechanisms in cancer cells such as DNA damage and ferroptosis. Toxic metabolite overloading is discussed as an emerging therapeutic strategy that carries potential advantages such as allowing tuning of toxicity via dietary control of metabolite production and exerting microenvironmental toxic effects to enhance overall efficacy in the heterogenous tumor.
