The effect of device type and radiation dose in intraoperative radiotherapy (IORT) for colorectal cancer is not well established. To explore this, we reviewed studies reporting postoperative complications, disease-free survival, local control, and long-term survival in patients treated with non-implantable IORT techniques-IOERT, KV-IORT, and HDR-IORT. Most of the available evidence relates to IOERT or HDR-IORT, which is usually delivered at 15 Gy (range 10-20 Gy). The median dose for KV-IORT is typically 12.5 Gy.

We conducted a systematic search of literature through November 2023 to identify studies that compared non-implantable IORT with surgery alone or other treatment approaches (PROSPERO registration: CRD42024508349). Twenty-five studies involving 2664 patients met the inclusion criteria.

Patients treated with non-implantable IORT tended to achieve better 5-year overall survival than those managed without it, with IOERT contributing most clearly to this difference. A similar pattern emerged for long-term local control, where IORT showed an advantage [OR 2.08, 95% CI 1.19-3.64]; studies of IOERT reported an even stronger effect [OR 2.23, 95% CI 1.07-4.65]. Importantly, the use of IORT did not correspond with higher rates of key postoperative complications, including anastomotic leakage, pelvic collections, wound problems, or bowel obstruction.

Our results suggest that IORT may improve survival and local control for patients with advanced or recurrent colorectal cancer, despite the heterogeneity among studies. Device-related and dose-related factors may also play a role and merit closer study, thus warranting closer examination in future work.

Radioactive iodine (RAI) therapy is often administered post-total thyroidectomy in patients with low-risk differentiated thyroid carcinoma, despite guidelines advising against its routine application. Evidence regarding the efficacy of RAI in reducing recurrence and improving survival in low-risk differentiated thyroid cancer (DTC) remains inconsistent.

We conducted a systematic review and meta-analysis of observational studies and randomized clinical trials that compare RAI versus no RAI in low-risk DTC patients. Databases such as MEDLINE, Scopus, Cochrane Library, and Google Scholar were searched through December 2025. Outcomes included recurrence, recurrence-free survival, treatment response, biochemical markers, and side effects. We performed statistical analysis using Review Manager (RevMan) 5.4 with a random-effects model, reporting odds ratios (OR) with 95% confidence intervals, and significance set at p < 0.05. Heterogeneity was assessed using I² statistics.

Ten studies (n = 5260) were included in the analysis. No statistically significant difference was observed between the two groups for recurrence (OR 0.66, 95% CI: 0.41-1.08; p = 0.10), 5-year recurrence-free survival (OR 2.47, 95% CI: 0.63-9.62; p = 0.19), or treatment response (excellent response: OR 1.00, 95% CI: 0.52-1.92; p = 1.00). Secondary outcomes, including serum thyroglobulin > 1 ng/mL (OR 1.20, 95% CI: 0.00-342.55; p = 0.95), elevated thyroglobulin antibodies (OR 0.91, 95% CI: 0.38-2.16; p = 0.83), xerostomia (OR 5.63, 95% CI: 0.05-667.24; p = 0.48), and dysphonia (OR 0.96, 95% CI: 0.53-1.72; p = 0.88), were also not significantly different between groups, although estimates were not precise.

The available randomized and observational evidence does not demonstrate a clear, clinically meaningful benefit of routine RAI ablation in patients classified as low-risk DTC. These findings should be interpreted with caution due to heterogeneity across studies, variability in outcome definitions, and the predominance of observational data.

Insulin resistance (IR) is involved in the development, progression, and treatment resistance of cancer. Apart from contributing to obesity and type 2 diabetes, IR leads to hyperinsulinemia, disruption of insulin-like growth factor signaling, chronic inflammation, and metabolic remodeling, which fosters a pro-tumorigenic milieu. These changes stimulate the PI3K-Akt-mTOR, MAPK, JAK-STAT, and NF-κB pathways, which increase proliferation, survival, angiogenesis, immune escape, and metastasis. IR also modifies the tumor microenvironment (TME) and dampens anti-tumor immunity. IGF-1R, IL-6, IL-1β, TNF-α, PD-1, PD-L1, and CTLA-4 monoclonal antibodies could be beneficial by inhibiting inflammatory and oncogenic pathways and reinitiating immune surveillance. Tumor resistance and heterogeneity are significant obstacles. This is a structured narrative review of the molecular connections, antibody treatments, translational obstacles, and future refined approaches in oncology.

DNA double-strand breaks (DSBs) are the most severe DNA damage, and defective repair can lead to apoptosis or malignant transformation. DSBs are mainly repaired by nonhomologous end joining (NHEJ) and homologous recombination (HR), while microhomology-mediated end joining (MMEJ) serves as a backup pathway. Since DNA polymerase theta (Polθ) is essential for MMEJ, this pathway is also named Polθ-mediated end joining. Polθ is barely expressed in normal tissues but overexpressed in many cancers, making it a promising therapeutic target. In recent years, Polθ inhibitors and related therapeutic strategies have emerged rapidly, with clinical trials underway. This review summarizes the structure, function and expression of Polθ in tumorigenesis, highlights synthetic lethal strategies, drug development and clinical translation, and discusses current limitations and future directions for cancer research.

Fc-gamma receptors (FcγRs) regulate IgG antibody activity, and Fc-engineering is a proven method to improve the efficacy of tumor-targeting antibodies. Here, we explore tailored FcγR blockade to enhance the therapeutic efficacy and tolerability of immune checkpoint-blocking (ICB) antibodies.

Mechanistically matched murine surrogate and human lead FcγR-blocking and immune checkpoint-blocking antibodies were used to study whether tailored FcγR-blockade, targeting FcγRIIB selectively or all FcγRs, can enhance the efficacy and overcome resistance to immune checkpoint therapy in vivo and in vitro. Mechanistic studies were performed with clinical reagents, including ipilimumab, nivolumab, pembrolizumab, and human FcγRIIB-selective (BI-1607) and pan-FcγR-blocking (BI-1206) antibodies, using human cells and transgenic animals with clinically relevant expression of immune checkpoint receptors.

We demonstrate that FcγRIIB-selective and pan-FcγR-blocking antibodies increase the in vivo efficacy of αCTLA-4 and αPD-1 antibodies, respectively. FcγRIIB-selective antibody enhancement of αCTLA-4 was associated with increased intratumoral Treg depletion, myeloid reprogramming, interferon-γ and CXCL10-induction, and increased activated effector CD8⁺ T cells, correlating with higher activating-to-inhibitory (A:I) FcγR engagement ratios. Conversely, pan-FcγR blockade protected αPD-1-coated T cells from macrophage phagocytosis, increasing intratumoral activated CD8⁺ T cells by decreasing activating and inhibitory FcγRs.

Our studies provide in vivo proof of concept that tailored FcγR blockade enhances immune checkpoint therapy and overcomes resistance through mechanistically distinct pathways. Clinical trials with tailored human FcγRIIB-blocking antibodies are ongoing.

CD3-bispecific antibodies (CD3-BsAbs) represent an emerging modality with promising anticancer potential. Despite increasing regulatory approvals, the development of CD3-BsAbs remains challenging. CD3-BsAb candidates are routinely assessed and compared via in vitro workflows. However, protocol heterogeneity across experimental laboratories constrains cross-study potency comparisons. To address this, we developed an in vitro Quantitative System Pharmacology (QSP) model that mechanistically characterizes key processes underlying CD3-BsAb activity. The aim was to establish a framework adaptable to diverse in vitro conditions. The current framework comprises (a) single-cell trimer formation sub-model, (b) trimer-mediated T-cell activation and differentiation sub-model, (c) effector T-cell mediated tumor cell killing sub-model. We evaluated the framework using DuoBody-CD3x5T4 (CD3 equilibrium dissociation constant (K_D) = 683 nM) data from 14 solid tumor cell lines spanning 5T4 expression of 9,447-61,686 molecules/cell and drug concentrations of 1.76E-05-42.8 nM. For a subset of cell lines, we also included additional data comparing DuoBody-CD3x5T4 with bsIgG1-CD3x5T4 (CD3 K_D = 16 nM) and assessing effector-to-target (E:T) ratios of 1:1-8:1. All in vitro data were pooled into a single modeling dataset. A joint fit of T-cell activation and tumor cell cytotoxicity across the interconnected sub-models accurately captured the data and demonstrated mechanistic consistency. The model yielded mechanistically meaningful parameters, such as the per-T cell trimer count required to achieve half-maximal T-cell activation (EC50_act, estimated to be 2.12-4.6 trimers/T cell). The model's mechanistic structure and versatility suggest its potential to serve as a platform to predict drug effects across diverse assay conditions, quantify assay-dependent effects, and guide candidate selection.

Oral malignant melanoma (OMM) is a rare and aggressive malignancy, and involvement of the tongue is particularly uncommon. We report a case presenting with two isolated pigmented tongue lesions clinically resembling benign conditions. Excisional biopsy of the anterior lesion confirmed melanoma, and the tongue base lesion was clinically suspected to represent possible in-transit metastasis. To our knowledge, in-transit metastasis in OMM is not well documented. The patient underwent wide local excision followed by adjuvant pembrolizumab based on cutaneous melanoma guidelines. Final pathological staging was pT3b pN1c cM0 (stage IIIC). At 1-year follow-up, no recurrence or metastasis was observed and oral function was preserved with a palatal augmentation prosthesis. This case highlights diagnostic challenges and the importance of early biopsy and multidisciplinary management. Additional cases and further multicentre studies are needed to validate these observations and guide the development of standardised treatment protocols in the diagnosis and management of OMM.

Pulmonary alveolar proteinosis (PAP) is a rare condition characterised by impaired alveolar macrophage-mediated surfactant clearance, resulting in the accumulation of lipoproteinaceous material within the alveoli. Secondary PAP has been associated with certain medications. Ruxolitinib, a Janus kinase 1/2 inhibitor has recently been implicated in rare cases of PAP.We report the case of a woman in her early 60s treated with ruxolitinib for chronic pulmonary graft-versus-host disease following an allogeneic haematopoietic stem cell transplant for acute lymphoblastic leukaemia, who developed progressive exertional dyspnoea. High-resolution CT demonstrated a 'crazy paving' pattern, and bronchoalveolar lavage revealed periodic acid-Schiff positive granular material consistent with PAP. Microbiological studies were negative. Ruxolitinib was discontinued with subsequent symptomatic, radiological and lung function improvement.This case highlights ruxolitinib as a potential cause of secondary PAP and emphasises the importance of considering this rare complication in patients who develop new respiratory symptoms while receiving ruxolitinib.

Chimeric antigen receptor (CAR) macrophage therapy shows significant potential for solid tumors owing to the intrinsic tumor infiltration and phagocytic capacity of macrophages. However, its clinical translation is limited by macrophage phenotypic plasticity within the immunosuppressive tumor microenvironment and the complexity of ex vivo cell manufacturing. It is essential to develop techniques that enable macrophages to be activated specifically by antigens while sustaining their proinflammatory activity in vivo.

Here, we report a mannose-modified lipid nanoparticle (LNP) platform for the co-delivery of CAR-encoding messenger RNA (mRNA) and the Toll-like receptor (TLR) 7/8 agonist resiquimod (R848), enabling in situ generation of proinflammatory CAR macrophages. In vitro, we assessed macrophage-preferential uptake, CAR expression efficiency, TLR7/8 agonist-mediated macrophage polarization, and immune activation. In vivo efficacy was assessed in syngeneic and humanized mouse models of triple-negative breast cancer, including postoperative recurrence and lung metastasis models.

Systemic administration of M-LNP/CAR+R848 induced robust CAR expression in tumor-associated macrophages and promoted sustained M1 polarization. Engineered macrophages exhibited enhanced antigen-specific phagocytic activity and tumor cell clearance, and promoted CD8+ T cell proliferation and NK cell infiltration, thus coordinating innate and adaptive immune responses. Functional macrophage depletion experiments demonstrated that tumor control was dependent on macrophages. In vivo treatment significantly reduced the growth of primary tumors, prevented postoperative recurrence, and prolonged survival in mice with lung metastases in both syngeneic and humanized models.

Our findings demonstrate that M-LNPs enabling co-delivery of mRNA and an innate immune agonist enable in situ generation of proinflammatory CAR macrophages and induce durable antitumor immunity. This controllable and non-integrative strategy allows tunable immune activation, provides a flexible platform for CAR macrophage-based immunotherapy in triple-negative breast cancer.

The peritumoral microenvironment has emerged as a key role in affecting tumor invasion and immunotherapy responses. In adipose-enriched tumors, such as breast cancer (BC), peritumoral adipose tissue (PA) harbors unconventional immune populations, yet its immunological functions remain poorly understood. In particular, how adipocyte regulate innate-like lymphocytes, such as γδ T cells, remains unclear.

We performed single-cell RNA sequencing and spatial profiling of paired specimens from patients with BC. Integrated multi-omics analyses, immunofluorescence staining, human γδ T-cell expansion assays, functional assays, and in vivo models were used to define the immune cell states and evaluate the impact of lipid mediator leukotriene B4 (LTB4) on γδ T-cell activation and signaling. Clinical correlations were assessed using our cohort and patient datasets.

We identified a previously unrecognized population of NKG2A⁺γδ T cells with predominant Vδ2 usage that preferentially accumulated in PA, particularly at the adipose-tumor interface. Multi-omics analyses revealed that they exhibited potent cytotoxic activity and extensive interactions with dendritic cells, coordinating a local immune surveillance network. Mechanistically, peritumoral adipocytes showed enhanced activation of the 5-lipoxygenase pathway and secreted the lipid mediator LTB4, which selectively combined to LTB4 receptors, thereby activating STAT1 signaling in γδ T cells and upregulating NKG2A expression. NKG2A⁺γδ T cells were preferentially enriched in ductal carcinoma in situ and early-stage BC. These cells were also associated with favorable clinical outcomes across multiple adipose-enriched tumors. Assays using human specimens confirmed that LTB4 potentiated γδ T cell-mediated antitumor responses. Importantly, LTB4-programmed γδ T cells displayed superior killing capacity using in vitro and in vivo assays.

These findings redefine PA as an active immunological niche that programs γδ T-cell immunity through adipocyte-derived LTB4 signaling. Our study identifies NKG2A⁺γδ T cells as cytotoxic sentinels at the adipose-tumor interface during early tumor development, providing a rationale for leveraging LTB4-mediated γδ T-cell programming in translational cancer immunotherapy.