The BRCA1 and BRCA2 tumor suppressor genes are integral to the repair of DNA double-strand breaks. Therefore, germline pathogenic variants (PVs) in either of these genes are associated with an increased risk of developing hereditary cancers. For over 30 years, studies have demonstrated a well established and markedly increased lifetime risk of female breast cancer and ovarian cancer for individuals with a PV in BRCA1 or BRCA2. Additional canonical cancers include prostate cancer, pancreatic cancer for males and females, and male breast cancer. Several noncanonical cancers have also been reported in association with BRCA1 or BRCA2, including stomach cancer and endometrial cancer. This review summarizes the established and evolving cancer risks associated with germline PVs in BRCA1 or BRCA2 as well as current clinical management recommendations. With increased uptake and diversified utility of germline genetic testing, this summary provides a current overview for clinical management of both male and female individuals with a PV in BRCA1 or BRCA2.

Preserving T cell cytotoxic function during ex vivo expansion remains a major challenge for adoptive cancer immunotherapy. A synthetic immune niche (SIN) composed of immobilized CCL21 and ICAM1 was shown to improve T cell expansion while preserving cytotoxicity; however, it remains unclear which specific step of the T cell killing process is enhanced by the SIN stimulation. Here, we combined advanced imaging based on time-lapse microscopy with a mean-field model to analyze the distinct stages in killing of B16 melanoma cells by CD8[Formula: see text] T cells. This framework enabled us to resolve the tumor cell killing process into discrete steps throughout target cell engagement with SIN-treated T cells and lytic hit delivery. We found that tumor cell death is best explained by a multi-hit process, requiring approximately four discrete hits to trigger cell death. Model-based analysis identified a significant increase in the lytic hit-delivery rate, [Formula: see text], as the main kinetic change associated with the enhanced cytotoxicity of SIN-treated T cells. The target encounter rate, [Formula: see text], could not be reliably compared between conditions because it was practically non-identifiable in the untreated dataset. Global sensitivity analysis further showed that increasing lytic hit delivery has a stronger effect on tumour control than increasing target encounter rates. These findings fundamentally reorient our understanding of optimized T cell manufacturing, suggesting that the lytic execution step may be the primary rate-limiting bottleneck in this in-vitro system, and that engineering strategies targeting granule polarization or discharge warrant prioritization alongside affinity-enhancement approaches.

Immune checkpoint blockade (ICB) has demonstrated limited efficacy in microsatellite stable (MSS) colorectal cancer (CRC). The fibroblast growth factor receptor (FGFR) signaling pathway contributes to tumor immune evasion, yet its role in CRC remains insufficiently understood. We investigated the immunomodulatory effects of FGFR inhibition in combination with PD-1 blockade in murine CRC models. In vitro co-culture systems were used to evaluate T cell activation upon FGFR3 blockade. RNA sequencing and bioinformatics analyses, including The Cancer Genome Atlas (TCGA) dataset evaluation, were conducted to elucidate molecular mechanisms and clinical relevance. Combined FGFR inhibition and PD-1 blockade significantly reduced T cell exhaustion and promoted macrophage repolarization toward an antitumor phenotype. Transcriptomic profiling revealed upregulation of immune-related pathways and activation of immune-stimulatory genes. In vitro, FGFR3-specific monoclonal antibody treatment enhanced IFNg release following PD-1 blockade. Moreover, analysis of TCGA data demonstrated that high FGFR3 expression correlates with worse prognosis in CRC patients. Our findings suggest that FGFR pathway inhibition may enhance the efficacy of immune checkpoint blockade and provide a rationale for further investigation of FGFR-targeted combination strategies in MSS CRC.

Proton therapy offers a distinct physical advantage over photon radiotherapy through the Bragg peak dose concentration in target with both lower integral dose and finite path length, and sharper penumbra as compared to photons, collectively reducing radiation exposure to surrounding normal tissues and potentially improving the therapeutic ratio. However, this advantage is tempered by uncertainties, including range uncertainty and variable relative biological effectiveness. In this review, the authors summarize contemporary evidence supporting proton therapy across pediatric, central nervous system (CNS), head and neck, thoracic, breast, gastrointestinal, genitourinary, and hematologic malignancies, as well as reirradiation. The strength of evidence varies substantially by disease site. Proton therapy is well established in pediatric cancers and selected CNS tumors, where minimizing integral dose and late toxicity is especially important. Randomized trials have demonstrated clinically meaningful benefits in selected settings, including improved disease control and survival with proton craniospinal irradiation for leptomeningeal metastases and reduced toxicity with preserved disease control and survival benefit in oropharyngeal cancer. Conversely, randomized data in localized prostate cancer have not shown improved patient reported outcomes compared with intensity modulated photon therapy. Ongoing phase 3 trials across multiple disease sites are expected to further define the role of protons by clarifying comparative effectiveness, toxicity reduction, and cost-effectiveness relative to advanced photon techniques. Future progress will depend on improved patient selection, robust treatment planning, and emerging technologies including adaptive proton therapy, proton arc therapy, and FLASH radiotherapy.