Immunotherapy has emerged as a transformative approach in gastrointestinal (GI) cancers, addressing historically poor survival rates in advanced-stage disease. Immune checkpoint inhibitors (ICIs) targeting the PD-1/PD-L1 axis demonstrate remarkable efficacy in colorectal cancer with deficient mismatch repair (dMMR) or high microsatellite instability (MSI-H), exemplified by trials like NICHE-2 achieving exceptional pathological response rates. However, significant limitations persist, including resistance in some dMMR/MSI-H tumors, minimal efficacy in proficient mismatch repair (pMMR) tumors, and low overall response rates across most GI malignancies due to tumor heterogeneity and immune evasion mechanisms. Predictive biomarkers such as tumor mutational burden (TMB) and PD-L1 expression are crucial for optimizing patient selection, while hypermutated pMMR tumors with POLE mutations represent emerging therapeutic opportunities. In pancreatic adenocarcinoma, where survival remains dismal, combination strategies with chemotherapy and novel approaches like cancer vaccines show promise but lack transformative breakthroughs. Esophagogastric cancers benefit from ICIs combined with chemotherapy, particularly in MSI-H and HER2-positive tumors, while hepatocellular carcinoma has achieved significant progress with combinations like atezolizumab–bevacizumab and durvalumab–tremelimumab surpassing traditional therapies. Biliary tract cancers show modest improvements with durvalumab–chemotherapy combinations. Despite these advances, immunotherapy faces substantial challenges including immune-related adverse events, acquired resistance through cancer immunoediting, and the need for biomarker-driven approaches to overcome tumor microenvironment barriers. This review discusses key clinical trials, therapeutic progress, and emerging modalities including CAR T-cell therapies and combination strategies, emphasizing the critical need to address resistance mechanisms and refine precision medicine approaches to fully realize immunotherapy’s potential in GI malignancies.

The American Cancer Society estimates that over 152,000 new cases of colorectal cancer (CRC) were diagnosed in 2024, with more than 105,000 cases affecting the colon and 46,000 involving the rectum. CRC remains the second leading cause of cancer-related deaths in the United States, with an estimated 53,010 deaths in 2024. In the era of precision medicine, which incorporates molecular and environmental information into clinical decision-making, identifying patients harboring a deficiency in Deoxyribonucleic acid (DNA) repair allowed for targeted immunotherapies and significantly reduced CRC-related mortality. A significant advancement in this domain is the application of liquid biopsy, which has emerged as a promising tool for prognostication, guiding therapy, and monitoring treatment response in CRC. This review aims to comprehensively explore the role of liquid biopsy in colorectal malignancies, describing its practical applications, prognostic significance, and potential to revolutionize CRC management in the future. At the end, we also aim to show a schematic representation of showing integration of Circulating Tumor (Ct) DNA in routine clinical management of CRC. The highlight of this article is the structured and evidence-based schematic framework and its integration into future practice. The schematic pathway is designed to optimize ctDNA utilization across various stages of colorectal cancer management.

Renal cell carcinoma (RCC) is a biologically diverse malignancy with a rising global incidence and a high propensity for metastasis, particularly in its clear cell subtype. While traditional treatments have centered on surgery and targeted therapies, immunotherapy has emerged as a transformative approach in the management of advanced RCC. This review explores the evolution of immunotherapy in RCC, from early cytokine-based treatments to the advent of immune checkpoint inhibitors (ICIs) and their integration with tyrosine kinase inhibitors (TKIs). We detail the immunologic mechanisms underpinning these therapies, the rationale from preclinical models, and the pivotal clinical trials that redefined standard of care. Challenges such as immune resistance, tumor heterogeneity, and immune escape mechanisms are critically analyzed, highlighting tumor-intrinsic and microenvironmental factors. Lastly, we examine ongoing innovations including novel immune checkpoints, cytokine modulators, CAR-T therapies, and neoantigen-based vaccines, offering a forward-looking perspective on enhancing immunotherapeutic efficacy and personalization in RCC management.

Renal cell carcinoma (RCC) is a biologically diverse malignancy with a rising global incidence and a high propensity for metastasis, particularly in its clear cell subtype. While traditional treatments have centered on surgery and targeted therapies, immunotherapy has emerged as a transformative approach in the management of advanced RCC. This review explores the evolution of immunotherapy in RCC, from early cytokine-based treatments to the advent of immune checkpoint inhibitors (ICIs) and their integration with tyrosine kinase inhibitors (TKIs). We detail the immunologic mechanisms underpinning these therapies, the rationale from preclinical models, and the pivotal clinical trials that redefined standard of care. Challenges such as immune resistance, tumor heterogeneity, and immune escape mechanisms are critically analyzed, highlighting tumor-intrinsic and microenvironmental factors. Lastly, we examine ongoing innovations including novel immune checkpoints, cytokine modulators, CAR-T therapies, and neoantigen-based vaccines, offering a forward-looking perspective on enhancing immunotherapeutic efficacy and personalization in RCC management.

The effectiveness of immunotherapy and targeted therapy has been well established in metastatic renal cell cancer (mRCC). These therapies demonstrated higher overall response rates and led to prolonged survival. In contrast, in localized RCC, conventional treatment is either partial or complete nephrectomy. While surgery is a curative option in early stages, high recurrence rates remain a concern, with survival rates ranging from 53% to 85%, depending on the initial stage at the time of diagnosis. Given favorable outcomes with systemic therapies in the metastatic setting, there has also been an increased interest in utilizing these therapies for the localized stage with the rationale to eradicate the micro-metastatic clone, thereby reducing the recurrence rates. Despite these encouraging developments, challenges regarding the optimal timing, duration, and combination of systemic therapies are still under investigation. Adding to that, balancing the benefits of systemic therapies with potential toxicities is also crucial, especially in patients who might otherwise benefit from surgery alone. This review describes the current landscape, ongoing clinical trials, and future directions of systemic therapy in the management of localized RCC.

Duodenal metastasis from renal cell carcinoma (RCC), though rare, warrants consideration in patients with unexplained gastrointestinal (GI) symptoms. Endoscopic evaluation and immunohistochemistry (IHC) are essential for accurate diagnosis, while molecular profiling helps identify mutations influencing disease behavior and treatment response. Systemic therapy with targeted agents and immunotherapy requires careful monitoring due to potential toxicity. A multidisciplinary approach remains essential for optimizing management and surveillance strategies in metastatic RCC.