Renal cell carcinoma (RCC) is a heterogeneous malignancy with limited predictive biomarkers to guide treatment. Emerging evidence suggests that the microbiome might influence systemic immunity, therapeutic response and clinical outcomes. In metastatic RCC, the gut microbiome has been linked to the efficacy of immune checkpoint inhibitors, whereas the existence of a tumour microbiome remains a topic of debate. Circulating microbial DNA in blood has been proposed as a minimally invasive window into systemic immune status, offering a potential tool for monitoring treatment response, but its role in RCC is largely unexplored. Evidence from mechanistic studies, primarily from other solid cancer types, suggests that microbiome-immune crosstalk, microbial metabolites and functionally redundant pathways across taxa could modulate tumour biology. However, progress in RCC microbiome research remains limited by small cohorts, methodological variability and challenges in working with samples with a low microbial biomass, which are highly prone to contamination. Emerging spatial and multi-omics technologies now enable high-resolution mapping of these complex interactions, offering the potential to transform our understanding of the cancer microbiome. A structured roadmap is required to overcome technical and analytical challenges in RCC microbiome studies, enabling the identification of clinically relevant microbial signatures and their role in shaping tumour immunity. Here, the authors examine the evidence on the role of the microbiome in renal cell carcinoma, including methodological challenges that must be addressed to ensure reliability. Mechanistic hypotheses linking microbial signatures to immune modulation and treatment response are explored and the translational potential of these insights is considered, positioning the microbiome as a source of predictive and prognostic biomarkers and as a potential therapeutic target.
Relatively rare histologies of prostate cancer collectively account for <5% of all prostate cancers and comprise mucinous adenocarcinoma, intraductal carcinoma, ductal adenocarcinoma, neuroendocrine prostate cancer (including treatment-emergent small-cell neuroendocrine carcinoma), sarcomatoid carcinoma and basal cell carcinoma. These histologies have distinct morphological, molecular and clinical features from each other and the most common histological type, acinar adenocarcinoma. The perceived rarity of these histologies often reflects sampling limitations rather than biological prevalence, as many treatment-emergent phenotypes are seldom encountered in routine practice owing to the infrequent use of metastatic biopsies. These histologies demonstrate aggressive behaviour, atypical metastatic patterns and reduced responsiveness to conventional therapies. Despite their clinical importance, these entities remain under-represented in standard guidelines and clinical trials. Histological types and subtypes, such as ductal, mucinous, intraductal, neuroendocrine and sarcomatoid carcinomas, pose diagnostic and therapeutic challenges, and conventional screening with PSA exhibits limitations, so they are often diagnosed at advanced stages. Multiparametric MRI, immunohistochemistry and genomic profiling are crucial tools for accurate recognition and risk stratification. Histological type-specific genomic alterations, including DNA repair deficiencies, RB1 and TP53 loss, and mismatch repair mutations, provide potential therapeutic opportunities, but treatment recommendations are still largely extrapolated from acinar adenocarcinoma. Limited retrospective data suggest worse outcomes for patients with a rare histology than those with typical acinar adenocarcinoma, highlighting the urgent need for prospective registries and dedicated clinical trials. Rare histologies of prostate cancer are an under-recognized source of morbidity and mortality. Improved diagnostic precision, incorporation of molecular profiling and collaborative data collection efforts are essential to develop evidence-based strategies. In this Review, the authors address the clinicopathological features, available treatments and oncological outcomes associated with major rare prostate cancer histological subtypes, and highlight the need for improved approaches to enhance their clinical management.
Radical cystectomy is the current first-line treatment for patients with BCG-unresponsive non-muscle-invasive bladder cancer; however, this surgical procedure is associated with considerable morbidity and mortality. Bladder-preserving treatments, including single agents — such as nadofaragene firadenovec, a nonreplicating adenoviral-vector-based gene therapy; pembrolizumab, an immune checkpoint inhibitor immunotherapy; and single-agent intravesical chemotherapy using valrubicin or controlled-release gemcitabine — and combination therapies, including nogapendekin alfa inbakicept-pmln (an IL-15 receptor agonist immunotherapy) plus BCG — and multiagent intravesical chemotherapy (for example, gemcitabine plus docetaxel) are also recommended by current guidelines. Single-agent therapies can lead to development of acquired immune resistance; thus, combination therapies are a key area of interest for improving patient outcomes. Options for this approach include combinations of intravesical chemotherapy, BCG, immunotherapy, gene therapy and radiotherapy. These bladder-preserving combination therapies have the potential to change the treatment paradigm for patients with BCG-unresponsive non-muscle-invasive bladder cancer by improving clinical efficacy and avoiding the need for cystectomy. Future studies must evaluate the benefits and risks associated with combination treatment, considering patient convenience, toxicity, efficacy, the risk of progression and treatment cost. For patients with BCG-unresponsive non-muscle-invasive bladder cancer, bladder-preserving therapies are emerging as alternatives to radical cystectomy. This Review examines the biological rationale and clinical evidence for combination approaches involving chemotherapy, immunotherapy, gene therapy and radiotherapy, highlighting how synergistic strategies could overcome resistance and improve durable responses.
Treating bacterial infections, such as urinary tract infection (UTI), with antibiotics does not always resolve the infection and often results in subsequent re-infection. Treatment failure can be driven by bacterial mechanisms of resistance, tolerance or persistence, collectively known as the antibiotic non-response. Antibiotic resistance is well characterized across various bacterial species and implicated in poor clinical outcomes in various infection settings. In the instance of resistance, bacteria harbour genetic determinants to evade antibiotics and continue to grow during treatment. Notably, bacteria can escape antibiotic killing in the absence of resistance genes. In response to the environment, an entire bacterial population can slow its growth rate, becoming tolerant to bactericidal antibiotic exposure. Alternatively, a subpopulation of bacteria, known as persister cells, survive whereas the remainder of the population is eliminated by bactericidal antibiotics. Both mechanisms enable bacteria to survive treatment, with the capacity to regrow following cessation of antibiotic treatment. However, our understanding of tolerance and persistence in the context of UTI is limited. Thus, two bacterial phenotypes that might contribute to poor outcomes are overlooked both in the clinic and in research, which could add to the challenges of treatment failure and recurrent UTI. In this Perspective, different bacterial strategies that enable survival during antibiotic treatment are described, including antibiotic resistance, tolerance and persistence, in the context of urinary tract infection.
Whether patients with a solitary functioning kidney after kidney tumour treatment can safely participate in all sports remains debated, with inconsistent recommendations across guidelines. This Clinical Outlook provides personal and evidence-based considerations for safe return-to-play and proposes a practical classification of sports according to the specific risk of kidney injury.
