{
  "abstract": "The introduction of immune checkpoint inhibitors has changed how we treat advanced renal cell carcinoma (RCC). Durable responses, once rare, now occur in a meaningful proportion of patients treated with PD-1–based combinations. Yet, despite these advances, a familiar challenge remains: some tumours respond dramatically while others benefit little. Understanding the biology behind this variability is a major question in kidney cancer research.1 2Most studies of response and resistance mechanisms have examined metastatic lesions or old nephrectomy specimens collected before treatment. However, many patients receiving systemic therapy still have their primary tumour. As neoadjuvant and perioperative immunotherapy strategies grow, it becomes more important to understand how the primary tumour responds.",
  "authors": [
    {
      "affiliations": [
        "Department of Internal Medicine, Norton Community Hospital, Norton, Virginia, USA"
      ],
      "name": "Supriya Peshin"
    },
    {
      "affiliations": [
        "College of Medicine, Alfaisal University, Riyadh, Saudi Arabia"
      ],
      "name": "Ehab Takrori"
    }
  ],
  "full_text": "The introduction of immune checkpoint inhibitors has changed how we treat advanced renal cell carcinoma (RCC). Durable responses, once rare, now occur in a meaningful proportion of patients treated with PD-1–based combinations. Yet, despite these advances, a familiar challenge remains: some tumours respond dramatically while others benefit little. Understanding the biology behind this variability is a major question in kidney cancer research.1 2Most studies of response and resistance mechanisms have examined metastatic lesions or old nephrectomy specimens collected before treatment. However, many patients receiving systemic therapy still have their primary tumour. As neoadjuvant and perioperative immunotherapy strategies grow, it becomes more important to understand how the primary tumour responds.In this issue of BMJ Oncology, Tang and colleagues address this question using genomic and transcriptomic profiling of paired pretreatment and post-treatment primary RCC specimens from patients receiving immunotherapy.3 Their study offers a rare glimpse into the biological changes occurring within the primary tumour during treatment and provides important clues regarding both response and resistance. One of the most striking observations is that tumours destined to respond already appear immunologically distinct before therapy begins. Responding tumours were enriched for B-cell–related programmes, tertiary lymphoid structure (TLS) signatures, interferon signalling and other immune-related pathways. These findings align with a growing body of evidence suggesting that effective immunotherapy often depends less on generating a new immune response and more on reinvigorating an existing one.4–6 The presence of TLS-rich microenvironments has emerged repeatedly as a favourable feature across multiple tumour types and this study adds further support to their relevance in RCC.Equally interesting is what the investigators observed after treatment. Responding tumours showed a reduction in many immune-related transcriptional programmes, whereas non-responding tumours demonstrated increased inflammatory signalling and enrichment of exhaustion-associated pathways. The observation may seem counterintuitive at first sight. Yet, effective immune-mediated tumour clearance would predict reduced need for continuous immune activation. On the other hand, sustained inflammation in resistant tumours may be more indicative of a chronic, ineffective immune response as opposed to effective antitumour activity. Similar observations have been described in previous analyses of RCC treated with checkpoint blockade, highlighting the complexity of interpreting immune infiltration alone.4 7The study also highlights an increasingly appreciated role for tumour metabolism in determining therapeutic outcomes. Non-responding tumours showed enrichment of oxidative phosphorylation and fatty acid metabolism pathways. Experimental work has shown that these metabolic programmes can create conditions that impair T-cell function and promote immune escape.8 While these observations remain exploratory, they raise the possibility that overcoming metabolic barriers may represent an important avenue for improving immunotherapy efficacy.A major strength of this work is its longitudinal design. Paired tumour specimens obtained before and after immunotherapy remain uncommon, particularly from primary RCC tumours. The authors use changes over time rather than baseline characteristics to provide a more dynamic view of tumour evolution during treatment. Such data sets are difficult to generate and, therefore, especially valuable.Several limitations deserve consideration. The cohort is relatively small, particularly for paired analyses, and treatment approaches were heterogeneous. The study also relies primarily on bulk transcriptomic data, making it difficult to determine the precise cellular populations responsible for the observed changes. Future studies incorporating single-cell and spatial technologies will be important for validating and extending these findings.3 Despite these limitations, the study moves the field forward in an important way. Rather than focusing exclusively on static biomarkers, it emphasises that response and resistance are dynamic biological processes. The data suggest that the organisation and functional state of the immune microenvironment may be at least as important as the quantity of immune cells present.The next challenge will be translating these insights into therapeutic strategies. Can TLS formation be enhanced therapeutically? Can exhausted immune states be reversed before resistance becomes established? Can metabolic vulnerabilities be targeted to improve checkpoint inhibitor sensitivity? These questions will likely shape the next generation of translational RCC research.9 10For now, Tang and colleagues remind us that the primary tumour remains an important source of biological information. As immunotherapy continues to move earlier in the disease course, understanding the evolving relationship between tumour cells and the immune microenvironment within the kidney itself may prove just as important as studying metastatic disease.",
  "title": "Looking inside the primary tumour: what drives immunotherapy response in renal cell carcinoma?",
  "uid": "d6ad5b01-c530-59fd-9a88-8d6756fcddd9"
}