The demand for colonoscopies has increased over the last few years due to an aging population combined with a post COVID-19 backlog as well as an ongoing rise in younger patients with colorectal cancer (CRC). Quality indicators ensure that high quality colonoscopies are being performed by endoscopists, thus decreasing the risk of post-colonoscopy CRC arising from lesions missed on the index exam. One common outcome measure is known as the adenoma detection rate (ADR), which is the likelihood that an endoscopist will detect a pre-cancerous polyp during colonoscopy. The Artificial Intelligence (AI) program known as computer-aided detection system (CADe) was designed to improve the ADR of endoscopists by helping them identify colon polyps. Previous studies have evaluated the clinical outcomes of CADe but none were conducted in Hawai'i. This study was designed to determine the impact of GI Genius (Medtronic), the first CADe introduced in Hawai'i. Data was collected on aggregate ADR for both male and female patients before and after implementation of GI Genius in several ambulatory surgery centers in Hawai'i and then a cost-estimate analysis was performed. The GI Genius software program resulted in a statistically significant increase in ADR for both male and female patients. Furthermore, the addition of this program was found to be cost-effective when compared with standard colonoscopy alone due to an anticipated decrease in CRC related health care costs. CADe is a promising new tool for endoscopists, but further studies are needed to determine the long-term benefits on CRC incidence and mortality.

The preservation of the tumor immune microenvironment (TIME) ex vivo is essential for investigating tumor-immune interactions and developing effective immunotherapies. However, current culture models often fail to maintain autologous immune cells or support high-throughput testing. To overcome these limitations, we establish and validate a novel miniaturized-tumor culture (MTC) platform.

To build the MTC platform, we took tumor tissues from both mouse models and human patients. We processed these tissues into 100-500 μm fragments. Supplementation with IL-2 and IL-7 in culture maintained long-term intra-tumoral T cell survival. We then evaluated whether the platform could maintain autologous lymphoid populations and respond to immune checkpoint blockade (ICB), through co-culture assays with peripheral blood mononuclear cells (PBMCs) or splenocytes. The system accurately recapitulates drug response and resistance in both immunocompetent and immunodeficient models. Finally, we screened a high-throughput drug library to identify agents that re-sensitize tumors to anti-PD-L1 therapy. To figure out the underlying mechanisms, we used bulk RNA-sequencing, flow cytometry, and targeted CXCL13 antibody neutralization.

The MTC platform demonstrated better preservation of autologous lymphoid populations and remained responsive to ICB. Co-culture assays revealed enhanced immune cell infiltration upon ICB treatment. Furthermore, the MTC models recapitulated drug response and resistance phenotypes. Our screen identified axitinib (AXI) as the most potent agent for re-sensitizing tumors to anti-PD-L1 therapy across different cancer types. Mechanistically, AXI potentiates antigen presentation in tumor and dendritic cells. It also enhances cytotoxic T-cell function via the upregulation of CXCL13. Finally, CXCL13 blockade effectively abrogated AXI-induced T cell recruitment and tumor regression.

The MTC platform serves as a high-fidelity, high-throughput tool for modeling the TIME. It provides a valuable framework for developing novel anti-cancer strategies and elucidating their underlying mechanisms of action.

Magnetic hyperthermia (MH) has evolved from a localized thermal modality into an emerging intracellular immunomodulatory technology for cancer treatment. By employing magnetic nanoparticles (MNPs) to convert alternating magnetic fields into confined intracellular heat, MH enables precise spatial and temporal regulation of cellular stress responses while maintaining favorable biocompatibility and tumor selectivity. This review highlights recent advances that reposition MH as a cell-level immune regulation strategy, focusing on three interconnected aspects: (i) rational design of MNPs to optimize magnetic-to-thermal conversion efficiency and achieve precise intracellular heat transduction; (ii) integration of magnetic field-controlled MH with drug delivery and nano-heating modalities to enable synergistic intracellular regulation; and (iii) mechanistic insights into MH-induced immune modulation, including immunogenic cell death, immune cell activation, and its integration with tumor vaccines and cancer immunotherapy. Collectively, these advances establish MH as a versatile intracellular immunoregulatory platform and underscore its potential for precision cancer immunotherapy.

Carbonic anhydrase IX (CAIX) is an interesting therapeutic target in clear cell renal cell carcinoma (ccRCC), but gastrointestinal uptake impedes the clinical translation of CAIX-targeted radioligand. In this study, structure-guided optimization of a cyclic peptide scaffold was conducted to decouple tumor targeting from gastrointestinal retention.

Five novel CAIX-targeting ligands were developed at the base of a cyclic peptide and evaluated in OS-RC-2 cell, small animal positron emission tomography/computed tomography (PET/CT), biodistribution, and radiotherapy experiments. The lead candidate was tested on 21 patients with cancer in comparison to ¹⁸F-FDG.

In preclinical experiments, ⁶⁸Ga/¹⁷⁷Lu-ZH2 exhibited sub-nanomolar CAIX affinity and a favorable pharmacokinetics, with preserved tumor uptake and markedly reduced gastrointestinal retention, compared with benchmark ⁶⁸Ga/¹⁷⁷Lu-DPI-4452. In mice, ¹⁷⁷Lu-ZH2 inhibited tumor growth and prolonged survival without evident toxicity. In a first-in-human study of 21 patients with renal masses, ⁶⁸Ga-ZH2 PET/CT was deemed safe and demonstrated a superior diagnostic performance to ¹⁸F-FDG, detecting additional primary tumors and metastases with higher contrast.

These results establish ⁶⁸Ga/¹⁷⁷Lu-ZH2 as a CAIX-targeted imaging and potential therapeutic agent with favorable preclinical and early clinical imaging characteristics, enabling the sensitive detection of ccRCC and laying the groundwork for further therapeutic investigation.

Fusobacterium nucleatum (Fn) is associated with resistance to neoadjuvant chemo-immunotherapy in esophageal squamous cell carcinoma (ESCC), but the underlying mechanism is unclear. We identified Fn-induced SPP1⁺ macrophages as key drivers of a cancer-associated fibroblast (CAF)-mediated spatial immune barrier that restricts CD8⁺ T-cell infiltration.

Mannose-modified non-cationic thiourea lipid nanoparticles (NC-TNP^M) were engineered to deliver Cas9 mRNA and SPP1-targeting sgRNA to macrophages. Their therapeutic efficacy was evaluated in Fn-associated ESCC models combined with chemotherapy and anti-PD-L1 treatment.

NC-TNP^M achieved efficient SPP1 silencing, markedly reduced SPP1⁺ macrophages, disrupted the macrophage-CAF immune barrier, and restored intratumoral CD8⁺ T-cell infiltration. Combined with chemo-immunotherapy, NC-TNP^M significantly suppressed tumor growth, enhanced cytotoxic T-cell activity, promoted macrophage repolarization, and showed no evident toxicity.

Fn-induced SPP1⁺ macrophages drive immune exclusion and chemo-immunotherapy resistance in ESCC. Macrophage-targeted SPP1 editing with NC-TNP^M overcomes this barrier and enhances therapeutic efficacy, highlighting a promising nanomedicine strategy for ESCC.

TRIB3 is upregulated in non-small cell lung cancer (NSCLC) and associates with worse survival, yet targeted therapeutics remain lacking. Calcium phosphate (CaP) nanoparticles offer biocompatible, serum-stable delivery for siRNA therapy. Here, we developed CaP nanoparticles loading siRNA targeting TRIB3 (NP_CaP/siTrib3) and evaluated antitumor efficacy and mechanisms in vitro and in vivo.

NP_CaP/siTrib3 was synthesized via biomineralization, and RNase resistance was verified by PAGE. Mouse KP-1 NSCLC cells were used for transfection, apoptosis (Annexin V/7-AAD), migration (scratch), invasion (Matrigel Transwell), qRT-PCR, and Western blot of epithelial-mesenchymal transition (EMT) and stemness markers. C57BL/6 subcutaneous tumor models received tail-vein injections for efficacy and biosafety assessment.

TRIB3 was significantly upregulated in NSCLC tissues compared with normal lung tissues and was associated with poorer overall survival. NP_CaP/siTrib3 formed nanosheets with an average size of approximately 159.4 nm and exhibited a more negative zeta potential than bare CaP, indicating successful siRNA loading. The CaP shell effectively protected siTrib3 from RNase degradation. NP_CaP/siTrib3 efficiently silenced TRIB3 protein expression in KP-1 cells, with gene knockdown efficacy comparable to Lipo8000 but with lower cytotoxicity. Functionally, NP_CaP/siTrib3 significantly promoted apoptosis and inhibited cell migration and invasion. In vivo, intravenously administered NP_CaP/siTrib3, which primarily accumulated in tumors through the enhanced permeability and retention (EPR) effect, markedly suppressed tumor growth without affecting body weight. Mechanistically, NP_CaP/siTrib3 reversed EMT by upregulating E-cadherin and downregulating N-cadherin and Snail, and reduced cancer stemness by decreasing the expression of Sox2, Nanog, Pou5f1, Klf4, and c-Myc. Biosafety evaluations demonstrated negligible hemolysis, normal serum biochemistry and hematology, and no histopathological damage in major organs.

NP_CaP/siTrib3 is an effective and biocompatible siRNA nanoplatform that suppresses NSCLC progression through dual inhibition of EMT and cancer stemness, supporting TRIB3 as a promising therapeutic target.

Brain metastases with neuroendocrine differentiation are rare but well-documented and may closely mimic primary intracranial neoplasms. Their radiological and clinical overlap with high-grade glial tumors can complicate the initial diagnostic approach, particularly in young patients without a known primary malignancy. Accurate diagnosis is critical, as neuroendocrine tumors (NETs) require systemic evaluation and management strategies distinct from those of primary brain tumors.

A 22-year-old man presented with a first-time generalized tonic-clonic seizure accompanied by severe headache, generalized weakness, malaise, and progressive right-sided facial paresis and paresthesias, later extending to the right upper extremity. Brain magnetic resonance imaging demonstrated a left frontotemporal lesion with imaging characteristics suggestive of a high-grade astrocytoma. The patient underwent surgical resection via an extended pterional approach, achieving gross total resection of the lesion. Initial histopathological evaluation suggested a high-grade glioma. However, further immunohistochemical analysis of the solid tumor component revealed positivity for pancytokeratin (AE1/AE3), MOC31 (polyclonal), and synaptophysin (polyclonal), with a Ki-67 (MIB-1) labeling index of 10-15%. These findings supported a diagnosis of carcinoma with neuroendocrine differentiation, contradicting the initial presumptive diagnosis of a primary glial tumor. A postoperative octreotide scintigraphy (octreoscan) failed to identify a primary NET.

This case underscores the diagnostic challenge posed by brain metastases with neuroendocrine differentiation, particularly in young patients presenting with solitary intracranial lesions mimicking high-grade gliomas. It highlights the indispensable role of immunohistochemistry in establishing the correct diagnosis and guiding appropriate systemic evaluation and management. Awareness of this rare entity is essential, as misclassification may lead to suboptimal treatment strategies and delayed oncological workup.

Accurate intraoperative visualization is critical for reducing margin positivity during breast-conserving surgery for triple-negative breast cancer (TNBC). Second near-infrared (NIR-II) fluorescence imaging represents a promising approach for precision surgery by combining lesion detection with real-time guidance. Nevertheless, the clinical translation of most fluorescence agents remains hampered by carrier-related toxicity and complex synthesis. Therefore, a "green" drug-repurposing strategy was adopted here to construct carrier-free pure-drug nano-assemblies (PDNAs), aiming to provide a biocompatible and precise intraoperative navigation tool for TNBC resection.

We developed a novel PDNA system (CF-ICG) formed by the simple self-assembly of two clinically employed drugs: calcium folinate and indocyanine green. The targeting specificity of CF-ICG and the feasibility of NIR-II fluorescence-guided surgery were validated using MDA-MB-231-Luc xenograft and MMTV-PyVT transgenic models. A rapid ex vivo incubation protocol was developed to differentiate breast cancer from para-cancer tissues.

Driven by intrinsic Ca²⁺ from CF, CF-ICG was assembled through π-π stacking and electrostatic interactions, demonstrating stable physicochemical properties and FRα self-targeting ability. In vivo imaging provided high-contrast NIR-II signals for real-time surgical navigation and enabled precise identification of residual submillimeter tumor lesions (diameter ~0.9 mm) in MDA-MB-231-Luc xenograft models. It also clearly differentiated malignant from normal breast tissues in MMTV-PyVT transgenic mice (AUC = 0.941). Furthermore, the diagnostic performance of the rapid ex vivo incubation protocol was preliminarily validated using surgical specimens from TNBC patients (n = 11). Notably, this approach effectively differentiated tumors from para-cancer tissues within 12 min (AUC = 0.926).

By combining a "green" fabrication process with a drug-repurposing strategy, we developed CF-ICG as a carrier-free PDNA with tumor self-targeting capability, enabling precise intraoperative navigation in preclinical models and ex vivo tissues. These findings support the further development of this approach for more accurate tumor visualization and surgical decision-making in TNBC.

Colorectal cancer, a leading cause of mortality, is treated with surgery early and irinotecan (IRI) chemotherapy in advanced stages. Insulin-like growth factor-binding protein 3 (IGFBP-3), regulated by p53, mediates tumor suppression and apoptosis. This study evaluates the combined therapeutic effects of IGFBP-3 and IRI in colorectal cancer.

SW480 colorectal cancer cells were treated with IGFBP-3, IRI, and their combination; IC₅₀ values were determined by MTT assay, and combination effects were analyzed by CompuSyn. Oxidative stress markers, apoptosis, and cell cycle progression were assessed utilizing flow cytometry. Furthermore, caspase 3/7 activity was measured, and expression levels of Bax, Bcl2, and β-catenin were determined using RT-PCR.

The MTT assay revealed IC₅₀ of 8.4 μM for IRI and 43.03 nM for IGFBP-3, with CompuSyn confirming synergistic interaction (CI < 1). Compared to single agents, the combination treatment significantly enhanced apoptosis, induced greater G₂/M cell cycle arrest, and markedly increased levels of ROS, MDA, and protein carbonyls while significantly depleting GSH. At the molecular level, the combination synergistically upregulated pro-apoptotic Bax and downregulated anti-apoptotic Bcl2 and oncogenic β-catenin.

Our results indicated that IRI and IGFBP-3 show cytotoxicity, with IGFBP-3 enhancing IRI effect by inhibiting Wnt/β-catenin and increasing drug uptake, warranting assessment in normal cells.

The combination therapies are significantly more effective than monotherapies in enhancing anticancer efficacy, reducing drug-related toxicity, and lowering the risk of drug resistance in cancer treatment. However, achieving precise delivery of the drugs to the tumor site remains a major challenge. With the deepening exploration of surface-engineered nanocarriers, ligand-modified liposomal drug delivery systems (LLDDS) are constructed by integrating the active-targeting properties of functional ligands (such as peptides, glycans, and aptamers) with the inherent advantages of liposomes. LLDDS show promise for exhibiting strong tumor-targeting capability, improving pharmacokinetics, biodistribution, and therapeutic efficacy of anticancer agents, such as chemotherapy drugs, and enabling the multifunctional integration of multiple therapeutic strategies. This review summarizes the development of liposomes and ligand-mediated surface modification strategies. More significantly, the development of multifunctional liposomes, targeted delivery, improved anticancer effectiveness, and possible anticancer mechanisms are highlighted in the discussion of LLDDS's recent advancements for integrated therapy approaches in a variety of malignancies. Lastly, the potential and difficulties of clinical translation in this ever-evolving area are examined.