Triple negative breast cancer (TNBC) and ovarian cancer share many molecular features and are primarily treated with surgical resection and aggressive chemotherapy regimens. Unfortunately, survival rates for patients with advanced metastatic disease are poor, highlighting the need for innovative therapeutic approaches.

Using the DepMap database, we first sought to identify genes that were highly expressed and more essential for proliferation/viability in TNBC cells relative to other breast cancer subtypes. Candidate genes were validated using gene-specific siRNAs in a panel of TNBC and estrogen receptor positive breast cancer cells. CTPS1 expression, and its functional significance, was further evaluated in ovarian cancer models, including chemotherapy- and PARP inhibitor-resistant cell lines. Pharmacologic inhibition was assessed using STP938, a first-in-class selective CTPS1 inhibitor, in TNBC and ovarian cancer cells as well as in ex vivo and in vivo patient-derived xenografts (PDX).

Six genes (CTPS1, HUS1, PRKRA, RAD1, RAD9A, and RHOA) were identified as potential TNBC selective dependencies. Among these, CTPS1 was prioritized for further study given that it was highly expressed, further upregulated in chemotherapy- and PARP inhibitor-resistant cell lines, and resulted in the greatest anti-neoplastic effects when depleted. Knockdown of CTPS1 confirmed its selective essentiality and resulted in rapid and durable S-phase cell cycle arrest. Pharmacologic inhibition of CTPS1 with STP938 led to robust anti-neoplastic effects at nM concentrations across both chemotherapy-sensitive and -resistant TNBC and ovarian cancer cell lines. Significant anti-neoplastic activity was observed in 6 independent ex vivo ovarian cancer PDX models. Further, STP938 significantly inhibited progression of an ovarian cancer PDX model in vivo.

These findings identify CTPS1 as a critical dependency in TNBC and ovarian cancer. Selective pharmacologic inhibition of CTPS1 using STP938 is a potent inhibitor of tumor cell proliferation/viability and has anti-cancer activity in patient derived ex vivo and in vivo tumor models. These findings suggest that therapeutic targeting of CTPS1 represents an alternative approach for the management of patients with advanced and aggressive forms of these diseases.

Cancer continues to rank among the deadliest diseases globally, claiming numerous lives due to its high mortality rates. Chemotherapy, a primary form of cancer treatment, offers significant benefits but is hampered by drawbacks that compromise patients' quality of life. Consequently, developing minimally invasive treatment alternatives remains a formidable challenge. Among these, nanomaterial-based, light-activated phototherapies-including photodynamic therapy, photothermal therapy, and radiotherapy-emerge as promising options, providing precise spatial and temporal control with reduced invasiveness. Advances in nanoscience and engineering have led to the creation of nanoparticles (NPs) that integrate therapeutic and diagnostic capabilities, known as theranostics, which enhance the effectiveness of clinical cancer management. This review summarizes recent advancements in nanotheranostics, spanning optical to radio-based approaches. We discuss the roles of various nanomaterials, such as upconversion NPs, gold NPs, nano-scintillators, and mesoporous silica NPs, among others, highlighting their dual diagnostic and therapeutic functionalities. Furthermore, NP-mediated induction of programmed cell death mechanisms-ferroptosis, pyroptosis, and cuproptosis-underscoring their significance in targeted cancer therapies and immune modulation were also explored. Additionally, we discuss how NPs can activate the stimulator of interferon genes pathway, amplify antitumor immunity and offer new avenues for improving cancer treatment outcomes.

Innate immune signals encode functional instructions through temporal patterns such as oscillation frequency and duration-a principle validated at the single-cell level. Yet clinical evaluation of host responses in tumor immunotherapy remains dominated by "how strongly" the immune system is activated, while the waveform of the response-how it unfolds and when it resolves-is largely overlooked. This disconnect raises unresolved questions: why can tumor progression persist despite intense inflammation, and why is fixed-interval maintenance not universally effective? Intravesical BCG instillation offers a way forward: each instillation is a controlled stimulus, voided urine provides a noninvasive sampling window, and oncological plus bladder-function outcomes form a "controlled stimulus-noninvasive sampling-dual-endpoint" closed loop. Using this model, we propose a hypothesis organized around two observation levels. The fundamental unit is the single-instillation single-cytokine waveform-the complete concentration-time curve of one cytokine following one BCG dose; the second is the longitudinal waveform trajectory, which captures how such waveforms evolve across repeated instillations. Both levels reside at a mesoscopic interface between single-cell signaling dynamics and macro-scale clinical outcomes. Our central hypothesis is that temporal features of a single-instillation single-cytokine waveform-time-to-peak, elimination half-life, and decay morphology-carry predictive information independent of peak amplitude. Distinct waveform shapes may differentially instruct adaptive immune quality, while the decay phase defines the time window for immune homeostasis restoration, thus providing a biological rationale for individualized instillation timing. If validated, this framework would expand the evaluation paradigm for intravesical immunotherapy from an "amplitude" dimension to a dual "amplitude + waveform" paradigm.

The development of novel theranostic agents is a key initiative to address current limitations in disease diagnosis and therapy. Notably, targeting cyanine dyes (TCDs), by virtue of their excellent optical imaging performance, versatile structural modifiability, and multi-dimensional targeting specificity, facilitate the directional recognition of disease regions and exhibit tremendous application potential in theranostics. While a variety of TCDs have been successfully developed and their theranostic efficacy experimentally validated, researchers still lack a systematic summary of related studies. Although related advances in fluorescent probes, tumor theranostics, and NIR-II fluorophores have been reviewed, a focused and systematic overview of TCDs in terms of their synthesis, hierarchical targeting mechanisms, and multi-disease theranostic applications remains limited. Accordingly, this article systematically reviews TCDs' synthesis strategies, elucidates their "tissue-cell-organelle" hierarchical targeting mechanism, and summarizes the therapeutic applications in diseases including tumors, fibrotic diseases, metabolic diseases, and radiation-induced injuries. Compared with previous reviews, this review highlights the structure-inherent targeting properties of TCDs, their hierarchical targeting mechanisms, and their emerging theranostic potential beyond oncology. Meanwhile, this article outlines the core advantages and current challenges of TCDs in theranostic integration, and delineates key future directions, including precise and intelligent molecular design, photostability limitations, systematic preclinical evaluation, multimodal technology integration, and the expansion of disease application scenarios. It aims to provide comprehensive theoretical support for advancing the fundamental research and clinical translation of TCDs.

Recent advances in molecular and immunologic profiling have substantially refined the understanding of mycosis fungoides (MF) and Sézary syndrome (SS), the two most prominent subtypes of cutaneous T-cell lymphomas (CTCL). CTCL comprise a heterogeneous group of lymphoid malignancies characterized by clonal proliferation of malignant T-cell with cutaneous tropism. The pathogenesis of MF and SS appears to be driven by convergent oncogenic programs involving dysregulated JAK/STAT, NF-κB, PI3K/AKT/mTOR, and MAPK signaling, epigenetic reprogramming, apoptosis resistance, immune escape, and microenvironmental support. In parallel, altered surface phenotypes and chemokine receptor programs shape tissue tropism across skin, blood, and lymph nodes, while the tumor microenvironment promotes tumor persistence and Th2-skewed immune polarization. These insights have translated into novel targeted and immune-based therapies. This review summarizes current insights into the cell-intrinsic and microenvironmental biology of MF and SS and discusses emerging approaches aimed at achieving more durable and personalized disease control.

Obesity is a major global health challenge and an established risk factor for cancer. Beyond increasing tumor incidence, obesity reshapes the tumor immune microenvironment (TIME) through systemic metabolic reprogramming, adipokine dysregulation, chronic inflammation, and gut microbiota alterations. These systemic changes create spatially organized immunosuppressive metabolic niches, including adipocyte-rich, hypoxic/lactate-enriched, myeloid-dense, and CAF/ECM barrier regions. Such niches restrict effector T-cell and NK-cell function while supporting regulatory T cells, tumor-associated macrophages (TAMs), and myeloid-derived suppressor cells (MDSCs), collectively promoting tumor progression and therapy resistance. Obesity also generates context-dependent effects on immune checkpoint blockade (ICB), a phenomenon known as the "obesity paradox, " in which immune suppression coexists with increased checkpoint dependency. Understanding how obesity modulates tumor cell metabolism, immune-cell metabolic fitness, and stromal remodeling is essential for designing effective interventions. Therapeutic strategies combining metabolic modulation, ICB, lifestyle intervention, and microbiota-targeted therapies may convert obesity-driven immune suppression into actionable vulnerabilities. Integrating systemic metabolic indicators, immune-cell signatures, and spatial biomarkers will enable precision stratification of patients and inform combination immunotherapy strategies in obesity-associated cancers.

Glioblastoma (GB) remains one of the most aggressive brain tumours, with a median survival of 15 months, largely due to resistance towards available anti-cancer therapies, including cutting-edge immunotherapy. Growing evidence indicates involvement of cancer stem cells (CSCs) in escalating resistance against existing treatment modalities due to their phenotypic plasticity, elevated expression of drug-resistance pumps, and immunomodulatory behaviour. Such oncogenic consequences are regulated by several epigenetic reprogramming events that are pivotal in retaining adaptive traits associated with CSC-mediated therapy resistance and subsequent oncogenic progression. In this review, we consider such epigenetic consequences as "tumour memory" and try to shed light on the therapeutic vulnerabilities by targeting CSCs - the "carriers of tumour memory" - via immune interventions in GB. Interestingly, immune-based anti-cancer therapies are coming to the forefront of cancer research, where T lymphocytes are immunologically boosted to attack tumour cells. However, in reality, several constraints burden such procedures. Contextually, the GB microenvironment, dominated by bone marrow-derived cells, reprograms infiltrating immune cells into suppressor phenotypes, creating a "cold" immune landscape. The only zone where functionally active lymphocytes are preserved is the invasive margin of the tumour, where they undergo exhaustion along the TPE → TEX axis but retain proliferative potential. On this basis, we introduce the concept of "invasive margin lymphocytes" (IMLs), of which stem-like memory T cells (TSCM) are indispensable for long-term immunological protection, as they have unique proliferative potential and ability for long-term persistence. Incidentally, such TSCMs have striking similarities with CSCs, as both cell types employ evolutionarily conserved mechanisms of the WNT/β-catenin signalling pathway, hierarchical organisation, and DNA repair systems. Therefore, understanding CSC-TSCM bidirectional cross-talk could provide a heuristic basis for developing personalised TIL-based therapy aimed at suppressing the hierarchically organised CSC population and overcoming CSC-guided immunotherapy resistance. Drawing conceptual parallels between GB CSCs and TSCM, here in this review, we propose a three-stage therapeutic strategy: precision cytoreduction of the invasive margin, "warming up" the microenvironment using cancer vaccines and pharmacological agents, as well as adoptive transfer of TILs derived from the IML pool to ensure durable disease control.

T cell engagers (TCEs) have delivered meaningful clinical benefit to patients, with eight molecules currently FDA-approved for hematologic malignancies and two approved for solid tumor indications. Despite their transformative potential, successful TCE development across solid tumor indications remains challenging, and additional strategies are needed to maintain T cell fitness and function within the tumor microenvironment (TME). Next-generation TCE designs aim to increase response rate and bolster durability by optimizing or delivering additional signals to T cells. In recent years, cellular metabolism has emerged as a potent regulator of T cell function and fate, shaping immunity by supporting the biochemical requirements of immunological effector functions and acting as a direct immunoregulatory signal from the TME itself. Despite this, neither cell-intrinsic nor environmental roles for metabolism in regulating TCE responses in solid tumors have been explicitly explored. We propose that metabolism is a powerful lens for understanding TCE efficacy and resistance in solid tumors, integrating signals from both surface receptors and the biochemical environment of the TME to shape T cell function and therapeutic response. In this mini-review, we highlight how three classical T cell signaling axes - 1) the T cell receptor complex, 2) costimulatory receptors, and 3) cytokine receptors - drive metabolic rewiring to license immune function and shape T cell fate. We also explore how environmental cues such as nutrients or metabolic stressors govern T cell responses, highlighting how biochemical perturbations within the TME could hamper TCE efficacy. Finally, we highlight emerging methods for dissecting metabolic contributions to TCE responses, proposing that understanding the interplay between immunological signaling, cellular metabolism, and immune programming could inform the design of next-generation TCEs for solid tumors.

T cell-engaging antibody constructs (TCEs) have emerged as a potent modality to treat cancer and autoimmune diseases. Twelve TCEs have been approved by the FDA and EMA for the treatment of hematological malignancies or solid tumors. Despite the varying designs and binding properties, they all lead to robust single-agent efficacy and approvals in refractory or relapsed leukemia, lymphomas, multiple myeloma (MM), small cell lung cancer, EpCAM-expressing cancers or uveal melanoma. Where comparisons can be deduced, TCEs appear to achieve response rates like those obtained with CAR-T cell therapies. Given the success of the first generation of TCEs, considerable attempts are underway to further improve upon this modality. With the goal of expanding TCEs into other malignant and autoimmune indications, and to further enhance efficacy and improve safety, a multitude of novel TCEs are currently in preclinical and clinical development. Here we review the current approaches to developing next-generation TCEs that can widen the therapeutic index, address heterogeneous target expression, and thereby potentially improve efficacy and safety.

 Oncocytic thyroid carcinoma (OTC) and tenosynovial giant cell tumor (TGCT) are rare neoplasms with distinct biological behavior, and their coexistence has not been previously well documented. We report a rare case of concurrent recurrent OTC and diffuse-type TGCT (TGCT-D) in a 45-year-old man who presented with a rapidly enlarging soft-tissue mass involving the left ankle and foot. ¹⁸F-fluorodeoxyglucose positron emission tomography/computed tomography (FDG PET/CT) demonstrated intensely FDG-avid lesions in the thyroid bed consistent with recurrent disease, as well as a hypermetabolic infiltrative musculoskeletal lesion in the left ankle and foot, initially suspected to represent metastatic spread. However, histopathological examination of the ankle lesion established the diagnosis of TGCT-D. This case illustrates an important diagnostic pitfall in oncology imaging: FDG-avid musculoskeletal lesions in patients with known malignancy do not necessarily represent metastases. Careful integration of clinical information, cross-sectional imaging, particularly MRI, and histopathological confirmation is essential to avoid misdiagnosis and to ensure appropriate management.