Second near-infrared (NIR-II; 1000 to 1700 nanometers) aggregation-induced emission luminogens (AIEgens) hold great promise for imaging-guided precision tumor phototherapy yet are limited by the intrinsic trade-off between fluorescence brightness and photothermal performance. Existing design strategies often yield complex molecular structures while inadequately addressing this trade-off. Herein, we propose a "Minor Tweaks, Major Leaps" concept: Simple modification of the star NIR-II AIEgen 2TT-oC6B (less than 5% change in molecular weight) markedly improves both NIR-II fluorescence brightness and photothermal performance. The thus-obtained new NIR-II AIEgen, ST-CZ, ranks among leading phototheranostic agents, exhibiting a long emission maximum at 1082 nanometers, a high fluorescence quantum yield of 4.3%, and a great photothermal conversion efficiency of 69% in nanoparticles. Leveraging these superior properties, ST-CZ enables cerebrovascular imaging with an advanced resolution of 19.0 micrometers, and the derived multifunctional platform achieves tumor progression-associated vascular remodeling visualization and efficient metastatic tumor ablation via synergistic photothermal immunotherapy. This work provides a robust strategy for developing high-performance NIR-II AIEgens for advanced biomedical applications.

Resistance to standard-of-care therapies remains a major clinical challenge in the treatment of the most common breast cancer, the hormone receptor-positive (HR+) subtype. Cyclin-dependent kinase 4/6 (CDK4/6) inhibitors improve outcomes in early-stage HR+ disease, yet many patients relapse. Resistance mechanisms of relapsed tumors include genetic alterations, but in many cases, no genetic drivers are identified. Here, we investigated mechanisms underlying resistance to CDK4/6 inhibitors using breast cancer patient-derived models and tumors. We identified an unexpected, noncanonical nuclear function of fumarylacetoacetate hydrolase (FAH), an enzyme in the tyrosine catabolism pathway, as a driver of resistance. FAH translocated to the nucleus upon CDK4/6 inhibition, where it interacted with cyclin-dependent kinase 9 (CDK9), and promoted resistance. Nuclear FAH was enriched in tumors from relapsed patients, and inhibition of CDK9 reversed FAH-mediated resistance. These findings establish nuclear FAH as a biomarker of resistance and revealed CDK9 as a therapeutic vulnerability in CDK4/6 inhibitor-resistant HR+ breast cancer.

Breast cancer is the most commonly diagnosed cancer worldwide and a leading cause of cancer-related mortality in women. Despite therapeutic advances, treating advanced or recurrent cases is substantially hampered by drug resistance and the immunosuppressive tumor microenvironment (TME). Here, we report a breakthrough immunotherapeutic strategy using dual-targeted extracellular vesicles from pro-inflammatory M1 macrophages, hyaluronic acid (HA), and cyclic RGD (M1EV_HA/cRGD), which function as molecular bridges to physically link natural killer (NK) cells with cancer cells. Our platform simultaneously reprograms the hostile TME while activating potent antitumor immunity. HA is incorporated to engage CD44 receptors on NK cells and cRGD peptides to bind tumor-overexpressing integrins, establishing precision dual-targeting. M1EV_HA/cRGD could physically tether NK cells directly to tumors, and deliver inflammatory cytokines and miRNAs that transform the immunosuppressive TME into a pro-inflammatory battlefield, substantially amplifying immune activation. In vitro and in vivo studies demonstrate that M1EV_HA/cRGD significantly enhances NK cell clustering at tumor sites, activation status, and cytotoxic killing of breast cancer cells. Unlike single-targeted approaches, this dual-targeting mechanism achieves simultaneous TME reprogramming and enhanced immune-tumor engagement. M1EV_HA/cRGD is a paradigm shift in solid tumor immunotherapy that directly addresses breast cancer treatment failure, can overcome therapeutic resistance, and substantially improve patient survival outcomes.

The incidence of early-onset cancers (diagnosis before 50 years of age) has been steadily increasing globally, presenting a significant public health challenge. While genetic predispositions play a role, most cancers cannot be traced to heritable components. Furthermore, the rapid rise in the incidence rates of these cancers strongly suggests the influence of environmental factors that constitute the "exposome." This perspective article integrates recent findings linking climate change and broader planetary health challenges to pervasive inflammation in the development of chronic diseases, especially cancer. We propose that the complex interplay of anthropogenic climate change, biodiversity loss, environmental degradation, disruption of ecological systems, exposure to environmental pathogens and toxins, industrialized food systems, and consumption of suboptimal, proinflammatory diets containing high concentrations of ultra-processed foods, creates a procarcinogenic exposome that may be particularly important during critical developmental windows, leading to increased susceptibility to carcinogenesis relatively early in life. Framed through a planetary health perspective, this article synthesizes evidence on how large-scale ecological disruption alters the human exposome and contributes to chronic inflammation, metabolic dysregulation, immune dysfunction, and cellular damage, all recognized drivers of cancer development. Although our primary focus is on early-onset cancers, many of these mechanisms are relevant across the cancer continuum and may influence carcinogenesis throughout the life course. We highlight the need for transdisciplinary research and integrated solutions that address both individual behaviors and systemic environmental and policy changes to mitigate the growing burden of early-onset cancers.

Genome instability (GI) is a hallmark of cancer. GI is associated with accumulative DNA damage and tumor-specific defects in DNA repair. Multiple antitumor drugs have been developed to promote persistent GI and to drive DNA damage beyond a threshold that tumor cells can survive. However, regulatory roles of circular RNAs (circRNAs) in GI and DNA damage remain elusive. Through circRNA profiling and a small interfering RNA (siRNA)-mediated screen, we have identified a circRNA termed circRBM39(4,5,6), which is significantly decreased in breast cancer (BC) and disrupts DNA damage response. CircRBM39(4,5,6) inhibits breast tumorigenesis through increasing DNA damage and promoting sensitivity to the antitumor drug poly Adenosine Diphosphate (ADP-ribose) polymerase inhibitor (PARPi). Mechanistically, cytoplasmic circRBM39(4,5,6) interacts with replication protein A2 (RPA2), an essential DNA repair factor, through a 7-nt AG-rich motif and destabilizes RPA2 protein by facilitating HECT and RCC1-like domain 2 (HERC2)-mediated ubiquitination, thus repressing homologous recombination repair. Importantly, administration of in vitro synthesized circRBM39(4,5,6) substantially inhibits breast tumorigenesis, sensitizes BC cells to PARPi, and renders them susceptible to synthetic lethality (SL) in distinct breast tumorigenesis mouse models. Our findings highlight the interplay between circRNA and GI in cancers, and the SL of circRBM39(4,5,6) to PARPi provides strategies for RNA-based BC therapeutics.

Gliomas are diffusely infiltrative, requiring accurate and sensitive diagnostic tools during surgical resection. Mutations in isocitrate dehydrogenase enzyme (IDH) alter its normal activity and result in accumulation of a unique oncometabolite, 2-hydroxyglutarate (2HG), in tumor cells. However, IDH-wild-type (IDH-wt) gliomas are more common and typically more aggressive. Here, 86 human brain samples were analyzed by syringe touch spray mass spectrometry to evaluate molecular alterations in gliomas. Tandem mass spectrometry (MS/MS) experiments were performed to minimize isobaric and isomeric interferences, and a ratiometric approach (using only signals for endogenous compounds) was employed to improve reliability of the measurements. Multiple ratios for pairs of metabolite signal intensities were found to differentiate tumor samples from nontumor tissue and they stratified glioma subtypes by IDH mutation status and by tumor grade, with several ratios showing 100% agreement with independent clinical assignments (P < 0.0001, Mann-Whitney U test). Increased carnitine relative abundances were found across all glioma subtypes. Importantly, α-aminoadipate was significantly elevated in grade 4 glioma, which may correlate with increased tumor malignancy. Grade 3 gliomas showed markedly higher 2HG abundance than grade 4 samples. In addition, a selection of ratios showed a linear trend with varying tumor cell percentage. Overall, the multiple metabolic ratio alterations indicate a high degree of heterogeneity among glioma subtypes. Furthermore, there are metabolites that can differentiate glioma from nontumor tissue and this measurement can be made by a simple ratiometric method which has potential to be used intraoperatively for margin assessment without diverging from standard of care.

Cytoreductive surgery (CRS) combined with hyperthermic intraperitoneal chemotherapy (HIPEC) treats peritoneal carcinomatosis by circulating heated (42 °C) chemotherapeutic solutions intra-abdominally, but risks severe systemic hyperthermia due to inconsistent temperature control protocols. Conventional methods like cooled fluids, ice packs, and cooling devices often prove inadequate, with slow response times and limited precision during open surgery. This case underscores the need for vigilance regarding perioperative hyperthermia during HIPEC and suggests employing targeted temperature management (TTM) with a 33 °C target, which limited core temperature rise from 36.1 °C to 37.4 °C (Δ1.3 °C) over 90 minutes of HIPEC-lower than fluctuations in non-TTM cases. TTM's real-time feedback enables rapid, automated shifts from warming (CRS phase) to cooling (HIPEC phase), reducing reliance on multiple adjuncts and minimizing thermal deviations. This approach enhances patient safety, optimizes therapeutic delivery, and may improve outcomes in CRS-HIPEC.

Measurable residual disease (MRD) serves as a critical biomarker of prognosis, treatment efficacy, and clinical outcome. It captures the presence of residual tumor cells below the detection threshold of conventional microscopy. Multiparametric flow cytometry (MFC) offers a rapid, cost-efficient, and widely applicable platform for MRD detection through leukemia-associated immunophenotypes (LAIPs) and deviation-from-normal (DfN) antigen maturation patterns. This technique underpins a wide range of clinical applications, including risk stratification, therapeutic decision-making, and post-transplant surveillance.   This chapter outlines essential technical parameters for achieving high-sensitivity MRD detection across hematologic malignancies such as B-ALL, T-ALL, AML, MM, and CLL. Key topics covered include material required, reagent preparation, antibody panel design, sample processing and acquisition, gating strategies, and illustrative examples. Special emphasis is given to adaptations necessary for MRD monitoring following CD19-targeted therapies in B-ALL. By integrating rigorous methodology with evolving innovations, MFC continues to advance as a precise and expedient tool for MRD assessment, contributing significantly to personalized treatment strategies.

Immunophenotyping by multiparameter flow cytometry is a rapid and efficient technique to simultaneously assess and correlate multiple individual cell properties like size and internal complexity along with antigen expression in a population of cells. This method is utilized for rapid characterization of the blasts and classification of acute myeloid leukemia (AML) in both the peripheral blood (PB) and bone marrow (BM). This technique is not only useful in the initial diagnosis but also in monitoring and determining the prognosis of the disease through minimal residual disease (MRD) testing. This chapter provides an overview of procedures for specimen processing, staining, and immunophenotyping of AML and describes the principles of data analysis for AML classification and MRD testing.

Primary central nervous system lymphoma (PCNSL) is an uncommon and aggressive extranodal non-Hodgkin lymphoma confined to the central nervous system, including the brain, leptomeninges, spinal cord, and eyes. Although high-dose methotrexate-based induction remains the backbone of first-line therapy, long-term disease control remains challenging, particularly in older or frail patients and in those with relapsed or refractory disease. Recent genomic and multi-omics studies have reshaped the biological understanding of PCNSL by identifying recurrent alterations in MYD88, CD79B, PIM1, PRDM1, CDKN2A/B, HLA-related genes, B2M, CIITA, and immune checkpoint loci, which converge on B-cell receptor/Toll-like receptor signaling, NF-κB activation, immune evasion, and microenvironmental adaptation. These molecular insights have accelerated minimally invasive diagnostics, including targeted mutation assays, multigene circulating tumor DNA profiling, methylation-based approaches, and cytokine analysis in cerebrospinal fluid, vitreous humor, and aqueous humor. Targeted and immune-based therapies, including Bruton tyrosine kinase inhibitors, immunomodulatory agents, immune checkpoint inhibitors, mTOR inhibitors, and CD19-directed chimeric antigen receptor T-cell therapy, have shown variable degrees of clinical activity, particularly in relapsed or refractory disease. However, most evidence remains derived from early-phase trials, single-arm studies, retrospective cohorts, or small series, and treatment selection is not yet routinely biomarker-defined. This review summarizes current advances in molecular taxonomy, pathogenesis, diagnostic work-up, liquid biopsy, prognostic stratification, and therapeutic management of PCNSL, emphasizing how molecular and longitudinal biomarker data may inform individualized treatment and future clinical trial design.