Human leukocyte antigen (HLA)-based immunotherapeutics, such as tebentafusp-tebn and afamitresgene autoleucel, have expanded the treatment options for HLA-A*02-positive patients with rare solid tumors such as uveal melanoma, synovial sarcoma, and myxoid liposarcoma. Unfortunately, many patients of European, Latino/Hispanic, African, Asian, and Native American ancestry who carry non-HLA-A*02 alleles remain largely ineligible for most current HLA-based immunotherapies. This comprehensive review introduces HLA allotype-driven cancer health disparities (HACHD) as an emerging research focus, and examines how past and current HLA-targeted immunotherapeutic strategies may have inadvertently contributed to cancer health disparities. We discuss several preclinical and clinical strategies, including the incorporation of artificial intelligence (AI), to address HACHD. Last, we emphasize the urgent need for further research to better understand HLA allotype heterogeneity and its influence on tumor immunopeptidome-driven immune responses. We anticipate that these strategies will accelerate the development and implementation of both personalized and broad-spectrum HLA-based immunotherapies, and will ultimately improve cancer treatment across genetically heterogeneous patient populations worldwide.

Stem-like CD8+ T cells – characterized by high-level expression of the transcription factor TCF-1, and known as progenitor exhausted T (Tpex) cells – have emerged as crucial mediators of durable antitumor immunity. These cells demonstrate unique self-renewal capacity, multipotency, and enhanced responsiveness to immune checkpoint blockade therapy. This review synthesizes current understanding of Tpex cell biology, including their defining characteristics, tissue distribution, and functional importance in antitumor immunity. We focus particularly on innovative approaches to preserve and enhance T cell stemness through combination therapies, cytokine signal modulation, epigenetic regulation, tumor microenvironment modification, and microbiota-based interventions. The development of these next-generation immunotherapies targeting T cell stemness represents a transformative frontier in oncology, holding significant promise for improving therapeutic outcomes in cancer patients.

Recent advances in spatial multi-omics technologies and analytical methods are transforming our understanding of how cancer cells and their microenvironments interact to drive critical processes such as lineage plasticity, immune evasion, and therapeutic resistance. By linking cancer cell states, lineage plasticity, clonal dynamics, oncogenic pathways, and cellular interactions to their spatial context, these innovations provide deep biological insights and reveal clinically relevant molecular programs and spatial biomarkers. This review highlights key breakthroughs in spatial profiling and computational approaches, including integration with computational pathology, multimodal data, and machine learning to uncover important biological insights. We discuss challenges in spatial multimodal data integration and emerging clinical applications, and we propose a roadmap to accelerate clinical translation and advance precision oncology through spatially resolved, actionable, molecular insights.

It is widely recognized that cancer develops through a series of changes that modify the genomes of normal cells, enabling them to acquire new malignant properties. Epigenetic disruptions, which do not directly change the genetic sequence but rather influence how the genome is interpreted, have garnered significant attention as contributors to malignant transformation and progression. With the advent of new technologies to profile both the genome and epigenome of cancer cells simultaneously, the interplay between structural variation (SV) and epigenetic changes in malignancy is now an expanding field. In this review, we describe the key technological advances and highlight recent research exploring the relationship between SV and the epigenome in cancer.

Myeloid cell leukemia 1 (MCL-1), an antiapoptotic protein, belongs to the BCL-2 protein family and is an extensively studied anticancer target. MCL-1 inhibitors have been in development for decades but fall short on efficacy, toxicity, and side-effects. Recently, Brinkmann et al. shed light on the apoptosis-unrelated function of MCL-1 and its physiological role that could critically lead to MCL-1 inhibitor development.

Viral mimicry is a cellular state in which the reactivation of silenced transposable elements (TEs) leads to the accumulation of immunogenic nucleic acids, triggering innate immune pathways that resemble responses mounted against viral pathogens. Although they were first characterized in the context of epigenetic therapies, growing evidence indicates that other cancer treatment modalities – including radiotherapy, chemotherapies, and targeted therapies – can also induce TE reactivation and viral mimicry responses in cancer cells. This review synthesizes the current knowledge on treatment-induced TE-mediated immune responses in cancer, highlighting therapeutic strategies, shared and distinct molecular mechanisms, and their broader implications for tumor–immune interactions and treatment outcomes.

Chimeric antigen receptor T cell (CAR T) therapies are ‘living drugs’ in which T cells are genetically engineered to recognize and kill cancer cells. A major barrier to progress for CAR T targeting liquid and solid tumors is the poor persistence of these cells in vivo, which limits therapeutic efficacy. In this review, we summarize the field’s current understanding of CAR T persistence, including clinical observations, patient correlatives and multiomics approaches, and emerging cell engineering and manufacturing strategies. We also propose a conceptual framework for CAR T persistence to guide interpretation of clinical data and the design of more potent and efficacious CAR T therapeutics.

CX3CL1 (fractalkine) is a unique chemokine with dual roles in cancer biology, capable of exerting both tumor-promoting and tumor-suppressive effects. Acting through its receptor CX3CR1, CX3CL1 facilitates immune evasion, angiogenesis, metastasis, and tumor cell survival and proliferation by recruiting immunosuppressive myeloid-derived suppressor cells. Conversely, it can enhance antitumor immunity by attracting cytotoxic T lymphocytes, natural killer cells, and dendritic cells into the tumor microenvironment. CX3CL1 has also been implicated in promoting immunogenic cell death–induced anticancer immune responses. However, excessive expression of CX3CL1 may paradoxically suppress immune activation, highlighting the importance of dose and context in its application. CX3CL1-based gene or mRNA therapies, particularly in combination with immune checkpoint inhibitors, show promising potential for cancer treatment.

The tumor microenvironment (TME) imposes profound metabolic and functional constraints on immune cells, with mitochondrial dysfunction emerging as a pivotal driver of immunosuppression. While mitochondrial metabolism is well recognized for its role in energy production and cellular homeostasis, its dynamic regulation of immune cell activation, differentiation, and exhaustion within the TME remains underexplored. In this review we summarize insights into how TME stressors such as hypoxia, nutrient competition, and metabolic byproducts subvert mitochondrial dynamics, redox balance, and mitochondrial DNA (mtDNA) signaling in T cells, natural killer (NK) cells, and macrophages, thereby directly impairing their antitumor efficacy. We emphasize that the restoration of mitochondrial fitness in immune cells, achieved by targeting metabolites in the TME and mitochondrial quality control, represents a pivotal axis for adoptive cell therapies (ACTs) and TME reprogramming.

Ribonuclease-targeting chimeras (RIBOTACs) are innovative RNA-targeting molecules that combine small-molecule RNA binders with endogenous RNase L-recruiting moieties, enabling catalytic degradation of previously considered 'undruggable' transcripts. The unique mechanism of RIBOTACs allows them to circumvent limitations of existing RNA-targeted therapeutics, expanding their therapeutic potential in oncology.

The urea cycle (UC) is a vital metabolic pathway that is responsible for the disposal of nitrogen and the production of metabolites necessary for biosynthesis. UC dysregulation is common in various cancers and impacts on cellular metabolism and the tumor microenvironment (TME). In this review we explore alterations in the expression of UC genes and metabolites in tumors, focusing on their roles in tumor progression, the TME, and cancer therapies. We discuss the effects of the UC on immune responses involving T cells and immunosuppressive cells, as well as on stromal cells and angiogenesis. We highlight the impact of arginine and polyamine metabolism in the TME. Although therapeutic strategies targeting the UC show promise, including arginine deprivation therapy (ADT), they face challenges such as drug resistance and toxicity. It will be essential to elucidate the specific functions of UC enzymes in tumorigenesis to devise more effective, personalized tumor therapies. Future studies should focus on combination therapies and personalized medicine to improve efficacy and patient prognosis.

Chimeric antigen receptor (CAR)-T cell therapy has shown significant clinical benefit in hematologic malignancies but remains less effective in solid tumors due to multiple barriers, including limited tumor infiltration, immunosuppressive microenvironments, and heterogeneity or imperfect specificity in tumor-antigen expression. ‘Armoring’ CAR-T cells to express chemokine receptors, enzymes that degrade extracellular matrix components, proinflammatory cytokines, or factors that modulate immunosuppressive signals could empower CAR-T cells to overcome barriers associated with solid tumors. However, translating promising preclinical results into reliable clinical benefit for patients with solid tumors remains challenging. This review critically examines emerging CAR-T cell armoring approaches and highlights key translational hurdles and the need for innovations in human-relevant disease models, safety designs, and treatment strategies for effective translation.

Colorectal cancer (CRC) remains one of the most prevalent cancers, with treatment largely dependent on surgery and chemotherapy, underscoring the need for novel or adjunct therapies. Cancer cells reprogram their lipid metabolism to support proliferation, invasiveness, and chemoresistance, making it a promising therapeutic target. Although several inhibitors of lipogenesis, lipases, lipid uptake, and lipid storage are under investigation in CRC, none have yet shown sufficient efficacy. Importantly, the tumor microenvironment (TME) and the microbiome influence CRC lipid metabolism by supplying compensatory lipids and engaging in crosstalk that affects the efficacy of lipid-targeting therapies. This review describes the role of lipids in CRC and explores how the TME and the gut/tumor microbiome may contribute to current challenges in the development of effective lipid-targeting therapies.

Metastatic disease and therapy resistance pose significant challenges in the treatment of breast cancer. Recent studies by Rozalén et al. and Petroni et al. uncover a crucial role for IL-17A-producing γδT cells in liver metastasis and therapeutic resistance, offering new insights into the mechanisms underlying these processes.

Glucose restriction generally limits tumor growth. Recently, Wu et al. reported that glucose restriction inhibits primary tumors but promotes lung metastasis by forming a macrophage-dominated, natural killer (NK) cell-deficient pre-metastatic niche (PMN). This finding provides a new perspective on understanding the dual role of glucose metabolism regulation in cancer treatment.

Anastasaki and colleagues establish a previously unknown glutamate growth dependency in pediatric low-grade brain tumors (gliomas). Glioma cells hijack normal neuron-glial molecular circuits present d...

Cancer immunotherapy has transformed treatment but faces challenges such as immune evasion and toxicity. Polo-like kinases (PLKs), frequently dysregulated in tumors, are emerging as key immune modulators. Combining PLK inhibition with immunotherapy may overcome resistance, enhance antitumor responses, and improve clinical outcomes, offering an optimally efficient strategy for cancer treatment.

Tumor-infiltrating lymphocyte (TIL) therapy has emerged as a transformative approach in cancer immunotherapy, particularly following the recent US Food and Drug Administration (FDA) approval of lifileucel for advanced melanoma. This review synthesizes current insights into the immune correlates and mechanisms underlying the efficacy of TIL therapy, highlighting the pivotal role of tumor immunogenicity, TIL functional states, and the tumor microenvironment (TME). Recent advances in single-cell profiling and biomarker discovery have enabled more precise patient selection and therapy optimization, while novel expansion protocols and engineered TILs are addressing resistance and broadening applicability to non-melanoma tumors. Collectively, these developments underscore the promise of next-generation TIL therapies to revolutionize treatment paradigms across a wider spectrum of solid cancers.

Retrotransposons are mobile repetitive elements that constitute around 43% of the human genome. Normally silenced through epigenetic mechanisms, retrotransposons can become reactivated in response to various stimuli, producing immunogenic DNA, RNA, and peptides that trigger innate and adaptive immune responses. In normal hematopoiesis, retrotransposon reactivation can drive inflammatory signaling responses, which support stem cell activity, influencing hematopoietic stem and progenitor cell (HSPC) regeneration. In hematological cancers, their reactivation can alter the tumor microenvironment and promote immune evasion. Here, we highlight the complex interactions between retrotransposons, hematopoiesis, and immune modulation. We also emphasize the therapeutic potential of targeting retrotransposons, while addressing critical knowledge gaps in retrotransposon-driven immune modulation across both health and disease.

T cell therapy has curative potential for many cancers. Despite impressive clinical efficacy in hematological malignancies, current T cell therapy still faces challenges related to sustaining responses, antigen escape, cytotoxicity, limited accessibility, and difficulties in treating solid tumors. The advent of CRISPR (clustered regularly interspaced short palindromic repeats) technologies provides a promising solution to these challenges. CRISPR technologies have grown from merely tools for gene knockout to sophisticated tools that can engineer cells at various levels of the genome, epigenome, and transcriptome. In this review we discuss recent technological advancements and how their application to T cells has the potential to steer the next generation of cellular therapy. We highlight emerging applications and current technological limitations that future tool development aims to overcome.

Phagocytosis upregulation plays a crucial role in bridging to adaptive immunity for cancer immunotherapy. However, current approaches to modulating phagocytosis are beneficial to certain types of cancer only. In this Forum paper, we will highlight how nanoengineering can overcome the current limitation of phagocytosis-mediated cancer immunotherapy.

Perineural invasion and cancer-induced nerve injury of tumour-associated nerves are associated with poor response to anti-PD-1 therapy, which can be reversed by combining anti-PD-1 therapy with a...