Immune checkpoint inhibitors (ICIs) have transformed cancer therapeutics yet frequently induce renal injury and multi-organ immune-related adverse events (irAEs) that present substantial clinical management challenges. Critical evidence gaps persist regarding dynamic immune microenvironment interactions and optimal organ-protective strategies.

We systematically evaluated ICI efficacy and safety profiles concerning renal and multi-organ outcomes in cancer patients, with particular focus on underlying mechanisms and protective interventional approaches.

We conducted a comprehensive, systematic literature search across PubMed, Cochrane Library, Embase, Web of Science, and Scopus (January 2000-December 2025) to inform a narrative synthesis. This narrative review approach integrates evidence from diverse study designs (experimental, observational, and clinical) to generate mechanistic hypotheses and clinical insights, rather than to estimate pooled effect sizes. Two independent reviewers performed structured study selection and quality appraisal using established tools (Cochrane RoB 2.0, ROBINS-I, GRADE) to enhance transparency and evaluate evidence certainty, acknowledging that formal meta-analysis was precluded by methodological heterogeneity. We employed narrative synthesis methodologies organized around mechanistic themes (PD-1/PD-L1 signaling, mTORC1-autophagy, cGAS-STING) to integrate translational and clinical evidence.

Our analysis of 68 included studies (n=15,392 participants) establishes that ICIs associate with acute kidney injury manifestations-notably tubulointerstitial nephritis-and multi-organ irAEs including myocarditis. Mechanistic investigations reveal PD-1/PD-L1 pathway disruption, metabolic dysregulation, and immune cell heterogeneity as central pathways, though quantitative effect estimates demonstrated significant interstudy variability.

Tumor immunotherapy substantially impacts renal and multi-organ homeostasis, supported by moderate-certainty evidence. Immune microenvironment-targeted protective strategies emerge as crucial for optimizing therapeutic outcomes, while future investigations should prioritize biomarker-guided precision approaches to balance efficacy and safety considerations. The observed heterogeneity in nephrotoxicity patterns suggests tissue-specific immune microenvironment interactions warranting single-cell resolution analysis.

Increased susceptibility to infections is observed in patients with thymomas. These have been invariably attributed to Good syndrome with hypogammaglobulinemia, but there is noticeable heterogeneity in clinical presentation. We clinically and immunophenotypically characterized the infective susceptibilities encountered in these patients.

Of thymoma patients recruited from Singapore and South Korea, their infection types were correlated against immunological parameters, including IgG, IgM, IgA, CD19+ B cells, and CD4+ T cells, and the presence of neutralizing anti-cytokine autoantibodies using direct ELISA. Lymphocyte subset immunophenotyping was performed. Ascertainment of immune signaling pathway disruption was through serum switch experiments. Respective immune signal outputs were probed using Western blotting.

A total of 15 thymoma patients (median age, 54 years; 13 men [87%]) were clustered into two groups with discernible differences in infective manifestations. In one group, nine patients (60%) had recurrent/severe viral or Pneumocystis jirovecii infections. These patients had low immunoglobulins and CD19+ B cells. The second group of six patients (40%) had difficult-to-treat non-tuberculous mycobacterium (NTM) or invasive bacterial or fungal infections. They had normal immunoglobulins levels and possessed autoantibodies against interleukin (IL-)-12, IL--23, or interferon-alpha (IFN-α), which consisted of anti-IFN-α2 and anti-IFN-ω subtypes. The autoantibodies consisted of a heterogeneous spread across IgG1 to IgG4 subclasses. These anti-IL--12, anti-IL--23, and anti-IFN-α autoantibodies were neutralizing and compromised various phosphorylated-STAT signaling pathways that are critical in host anti-pathogen response.

The dichotomy of infective manifestations (viral/PJP versus NTM/invasive bacteria/fungal) underlies distinct and novel immune susceptibility beyond the classic Good syndrome label in thymoma patients, with implications for different approaches to clinical management.

Among all the most prevalent malignant gastrointestinal cancers, colorectal cancer (CRC) occurs frequently in all the populations around the world. Despite remarkable advances in related research, substantial obstacles persist in the prevention and treatment of this malignancy, including safety concerns, adverse side effects, and tumor recurrence. Natural plant-derived compounds have increasingly attracted the attention of researchers in cancer research. Among these compounds, berberine (BBR) is a natural plant substance with multiple functions, which is extracted from Coptis Chinensis that possesses strong antitumor potential. Here we aim to investigate the effects and underlying mechanisms of BBR on CRC using several organoid models developed in our laboratory.

We firstly established CRC organoid models derived from KPC transgenic mice and Caco-2 cell line. CRC organoids were treated with different doses of BBR. The morphological characteristics, proliferation, ROS, apoptosis, and cell cycle were carefully evaluated. RNA-Seq assay, epithelial permeability, and lipid probes were also used to examine the underlying molecular mechanisms of BBR on CRC organoids.

BBR exhibited no harmful impact on healthy colonic tissues. However, BBR significantly inhibited the growth of both KPC organoids and Caco-2 organoids either at the early formation stage or after the maturity. BBR greatly decreased the ratio of Ki67 and EdU positive cells in CRC organoids and increased the level of ROS in organoids. RNA-Seq data implicated that BBR exerted direct cytotoxic effects on CRC organoids by inducing cell cycle arrest and breaking down the gap junctions. Immunohistochemical (IHC) staining identified the consistent changes of cell cycle arrest and dysfunction of epithelial barrier. FD4 staining showed increased epithelial permeability. Finally, LD540 probes and qPCR identified that BBR significantly blocked the lipid synthesis in CRC organoids.

In summary, our study identifies that BBR may suppress the malignant phenotype of CRC organoids via multiple mechanisms, including blocking cell cycle progression and disrupting lipid metabolism.

Peripheral T-cell lymphoma (PTCL) is a heterogeneous and highly aggressive subtype of non-Hodgkin lymphoma. Approximately 30% of patients develop relapsed or refractory PTCL (R/R PTCL) due to disease recurrence or failure to achieve complete remission after first-line therapy. Despite therapeutic advances, the molecular and cellular mechanisms underlying treatment resistance in R/R PTCL remain unclear.

Single-cell RNA sequencing and single-cell T-cell receptor sequencing were performed on seven tumor samples from six patients with R/R PTCL. These approaches were used to systematically characterize the transcriptional profiles of malignant T-cell clones and reactive T lymphocytes, define the transcriptomic landscape of R/R PTCL, and identify potential epigenetic biomarkers associated with drug response.

We observed significant upregulation of genes associated with cell proliferation, oncogenic signaling, and immune modulation in R/R PTCL. Within the tumor microenvironment, specific protumorigenic ligand-receptor interactions were identified, including CXCL13-CXCR5, CCL5-CCR5, and CD74-MIF interactions, which may facilitate immune evasion by malignant T cells. Longitudinal analysis of a patient who progressed following dual epigenetic therapy revealed marked downregulation of immune response-related genes, including HLA-DRA/DPA1/DRB5, CD74, C1QC, and LYZ, as well as functional reprogramming of tumor-associated macrophages. Enhanced LGALS9-HAVCR2 and CSF1-CSF1R interactions were also observed following combination treatment with chidamide and azacitidine.

This study delineates the transcriptional heterogeneity of malignant T-cell clones in R/R PTCL and suggests that this heterogeneity may contribute to resistance to epigenetic therapies. These findings provide novel insights into the molecular mechanisms underlying treatment resistance and highlight potential avenues for therapeutic intervention in R/R PTCL.

Oral epithelial dysplasia (OED) is a precancerous oral lesion with variable risk of progression to oral squamous cell carcinoma (OSCC). The molecular basis underlying this progression remains incompletely understood. To address this gap, this study applied spatial transcriptomics to characterize benign, OED and OSCC biopsies with a focus on the comparison between transforming and non-transforming OED.

Spatial transcriptomic profiling was performed on 13 benign, 15 OED (8 transforming, 7 non-transforming), and 14 OSCC biopsies using the NanoString GeoMx Digital Spatial Profiler. Regions of interest were segmented into epithelial and immune-enriched compartments with morphological markers. Gene expression was measured using the GeoMx Cancer Transcriptome Atlas (~1, 800 genes) and differentially expressed genes (DEGs) were identified using linear mixed-effects modeling. Exploratory bioinformatic analyses were performed to provide biological context.

Comparison of OED with and without transformation identified a limited set of 11 epithelial DEGs, including genes associated with antigen presentation and interferon signaling (e.g., B2M, STAT1, and CD74), while no significant DEGs were detected in immune-enriched regions. Pathway analyses indicated enrichment of immune- and interferon-related processes. Given the modest sample size and targeted gene panel, these findings should be considered exploratory in nature.

This study provides spatially resolved, exploratory insights into molecular differences between OED lesions with distinct clinical outcomes. The results suggest altered epithelial-immune interactions in transforming lesions, though these findings require validation. Spatial transcriptomics may offer a useful framework for investigating early molecular changes in oral carcinogenesis.

Breast cancer (BC) management has transitioned from histological classification to molecular subtyping, yet therapeutic resistance and intratumor heterogeneity remain critical clinical challenges. This review examines the emerging paradigm shift toward integrating mitochondrial metabolism into the precision medicine framework. We detail the complex mitonuclear crosstalk where nuclear genetic alterations, such as Breast Cancer 1 (BRCA1) deficiency and TP53 mutations, fundamentally reprogram mitochondrial bioenergetics. Specifically, the loss of BRCA1 function triggers a systemic NAD⁺ depletion trap through PARP1 hyperactivation, while oncogenic drivers like MYC coordinate with PGC1α to enhance mitochondrial biogenesis for metastatic survival. We evaluate the diagnostic potential of mitochondrial DNA heteroplasmy and machine learning derived metabolic gene signatures as high performance biomarkers for patient stratification and the detection of minimal residual disease via liquid biopsy. Furthermore, we analyze current clinical efforts to target mitochondrial vulnerabilities, including respiratory chain inhibitors like metformin and BH3 mimetics, while highlighting the significant challenges posed by metabolic plasticity and nutrient competition in the tumor microenvironment. The analysis of clinical trial data, such as the MA.32 study, suggests that metabolic interventions require precise patient selection based on specific metabolic phenotypes rather than broad application. Looking forward, the integration of genome scale metabolic models and artificial intelligence (AI) offers a transformative pathway to simulate patient specific metabolic fluxes and identify novel synthetic lethal targets. By bridging the gap between nuclear genomic drivers and dynamic mitochondrial adaptations, this review aims to provide a preliminary framework for the exploration of metabolic-genomic precision oncology in BC.

Background: Hidradenocarcinoma is a rare and highly aggressive malignancy with limited therapeutic options. This report describes the clinical course and treatment response of a patient with recurrent metastatic hidradenocarcinoma treated with sequential immunochemotherapy combined with anti-angiogenic therapy, with the aim of providing further insight into potential treatment strategies for this rare malignancy. Case Description: A 60-year-old male initially presented in 2020 with scrotal erythema and was diagnosed with hidradenocarcinoma after surgery. Despite surgical treatment, he developed recurrent disease with diffuse metastases. First-line chemoimmunotherapy (sintilimab, cisplatin, 5-fluorouracil; six cycles) achieved a progression-free survival (PFS) of 6 months. Following disease progression, second-line therapy (toripalimab, nab-paclitaxel, anlotinib; eight cycles) was administered, resulting in sustained stable disease with a subsequent PFS of 8 months. Radiotherapy was used for brain metastases. The total follow-up duration exceeded 4 years until the patient was lost to follow-up in December 2024. Conclusions: This case suggests that sequential programmed death-1 (PD-1) blockade-based immunochemotherapy combined with anti-angiogenic therapy may provide clinically meaningful disease control in metastatic hidradenocarcinoma, even in the setting of low programmed death-ligand 1 (PD-L1) expression and microsatellite stability. Our findings support a potential role for immunotherapy in sweat gland carcinomas and highlight the importance of individualized multimodal treatment strategies for this rare malignancy. Further studies are needed to identify predictive biomarkers and establish optimal therapeutic approaches.

Lung cancer in individuals who have never smoked (LCINS) represents a clinically and biologically distinct subset of non-small cell lung cancer, driven predominantly by oncogenic alterations rather than tobacco-related mutagenesis. This review aims to summarize current and emerging targeted and immune-based therapeutic strategies in LCINS individuals. These patients present a molecular profile that differs substantially from tobacco-associated disease and has direct consequences for treatment selection. Evidence published over the past five years has clarified how these molecular features shape treatment response and resistance in this setting. Particular attention is given to tumors with alterations in epidermal growth factor receptor, anaplastic lymphoma kinase, c-ros oncogene 1, rearranged during transfection, Mesenchymal-Epithelial Transition (MET) exon 14 skipping mutation, human epidermal growth factor receptor 2, valine-to-glutamic acid substitution at codon 600 of the BRAF gene (BRAF V600E), and neurotrophic tyrosine receptor kinase, which together comprise the dominant driver landscape in never-smoker lung cancer. Although third-generation tyrosine kinase inhibitors have markedly improved response rates in several of these subgroups, long-term disease control is frequently compromised by acquired resistance, and heterogeneous drug exposure, particularly in the central nervous system. By contrast, immune checkpoint inhibitors have yielded limited benefit, in keeping with the low mutational burden and generally low baseline immune activation observed in most LCINS tumors. As a result, alternative approaches such as antibody-drug conjugates, bispecific antibodies, and adoptive cellular therapies are being evaluated to address gaps left by existing treatments.

Immune checkpoint inhibitors (ICIs) combined with vascular endothelial growth factor tyrosine kinase inhibitors (VEGF-TKIs) have transformed the treatment landscape of advanced clear cell renal cell carcinoma (ccRCC). Current guidelines favour ICI plus VEGF-TKI (IO+TKI) combinations for favourable-risk disease (International Metastatic RCC Database Consortium [IMDC] score 0) based on improved objective response rates and progression-free survival. However, no IO+TKI combination has demonstrated a statistically significant overall survival (OS) benefit in this subgroup. A pooled analysis of four pivotal phase III trials (n = 839 favourable-risk patients) revealed no OS advantage for IO+TKI versus sunitinib monotherapy (hazard ratio [HR] 1.24; 95% CI 0.86-1.78) despite higher toxicity rates (71-82% Grade ≥ 3 adverse events vs. 63-72% with sunitinib) and substantially greater cost. The IMDC favourable-risk category represents approximately 20% of metastatic ccRCC cases and is often characterised by indolent disease biology. Emerging molecular classifications reveal distinct transcriptomic subgroups, including an angiogenic subtype (ccA/CC-e.2/clusters 1-2) enriched in favourable-risk patients, characterised by high hypoxia-inducible factor (HIF) pathway gene expression, frequent PBRM1 mutations, robust VEGF-TKI responsiveness, and comparatively lower benefit from immunotherapy. Current clinical risk stratification fails to capture this molecular heterogeneity, limiting optimal treatment selection. VEGF-TKI monotherapy (median OS 47.6-79.4 months) and active surveillance remain valid, evidence-based alternatives in carefully selected favourable-risk patients, particularly those with asymptomatic, metachronous, or otherwise indolent disease. Uncritical universal use of IO+TKI in this population may therefore represent overtreatment. The development and validation of predictive biomarkers, refinement of molecular risk stratification, and exploration of novel agents with more favourable toxicity profiles (e.g., HIF-2α inhibitors) are urgently required to personalise therapy and identify candidates for rational treatment de-escalation.

Breast cancer (BC) remains a leading cause of cancer-related mortality worldwide, and accumulating evidence suggests that tumor-associated microbiota may contribute to disease heterogeneity beyond host genetic and immune determinants. Advances in sequencing and multi-omics technologies have uncovered a reproducible intratumoral microbiome in BC, with distinct compositional patterns associated with molecular subtypes, clinicopathological features, and clinical outcomes. Alterations in specific microbial taxa have also been linked to tumor immune status, metastatic potential, and therapeutic sensitivity, underscoring their potential value in disease stratification and prognostic assessment. Although breast tissue represents a low-biomass environment, multiple studies employing stringent contamination control strategies have confirmed the reliability of these microbial signals. Experimental evidence further demonstrates that intratumoral microbes are functionally active components of the tumor microenvironment (TME), influencing tumor progression and metastasis through immune modulation, inflammatory signaling, and metabolic or hormonal reprogramming, while also shaping responses to chemotherapy and immunotherapy. This review summarizes current knowledge on the compositional features, functional mechanisms, and clinical relevance of the BC intratumoral microbiome, highlights methodological challenges in low-biomass profiling, and discusses future directions for translating these findings into clinically actionable strategies. The aim of this review is to systematically evaluate the role of the intratumoral microbiome in breast cancer pathogenesis and treatment, and to propose a framework for translating current findings into clinical practice.