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Understanding the Molecular Basis and Immunobiology of Renal Cell Carcinoma and Exploring Novel Therapeutic Strategies

A special issue of Cancers (ISSN 2072-6694). This special issue belongs to the section "Cancer Therapy".

Deadline for manuscript submissions: 30 June 2026 | Viewed by 573

Special Issue Editor


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Guest Editor
1. Department of Clinical Diagnosis and Clinical Education, Canadian Memorial Chiropractic College, Toronto, ON M2H 3J1, Canada
2. Department of Anatomy, Canadian Memorial Chiropractic College, Toronto, ON M2H 3J1, Canada
3. Department of Pathology/Microbiology, Canadian Memorial Chiropractic College, Toronto, ON M2H 3J1, Canada
Interests: renal cell carcinoma; miRNA research; biomarker discovery; precision medicine; molecular diagnostics; translational research
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Special Issue Information

Dear Colleagues,

Renal cell carcinoma (RCC) is the most common adult kidney neoplasm. It is an aggressive heterogeneous tumor with an unpredictable prognosis. Targeted therapies have significantly improved the metastatic renal cell carcinoma (mRCC) patient outcome. However, many refractory cases have been reported. A better understanding of the molecular basis and immunobiology of this aggressive tumor can pave the way toward the discovery of new therapeutic strategies for RCC.

We are pleased to announce our Special Issue, entitled “Understanding the Molecular Basis and Immunobiology of Renal Cell Carcinoma and Exploring Novel Therapeutic Strategies”, and invite you to contribute to it.

This Special Issue aims to provide a platform for developing a deep understanding of RCC pathogenesis, as well as recent advances in treatment choices in renal cell carcinoma to further optimize patient outcomes.

In this Special Issue, original research articles and reviews are welcome to be submitted. Research areas may include, but are not limited to, the following:

  • Molecular basis and immunobiology of renal cell carcinoma;
  • Biomarker discovery, including diagnostic, prognostic, and predictive biomarkers;
  • Recent advances in RCC diagnosis;
  • Molecular diagnostics;
  • Innovative therapeutic options for RCC.

We look forward to receiving your contributions.

Dr. Heba Khella
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as communications are invited. For planned papers, a title and short abstract (about 250 words) can be sent to the Editorial Office for assessment.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cancers is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • renal cell carcinoma
  • molecular basis
  • immunobiology
  • tumor microenvironment
  • immunotherapy
  • targeted therapy
  • metastasis
  • precision medicine
  • biomarkers
  • non-coding RNA
  • miRNA
  • prognosis
  • molecular diagnostics
  • translational research

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Published Papers (1 paper)

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Review

30 pages, 1934 KB  
Review
Low pH, High Stakes: A Narrative Review Exploring the Acid-Sensing GPR65 Pathway as a Novel Approach in Renal Cell Carcinoma
by Michael Grant, Barbara Cipriani, Alastair Corbin, David Miller, Alan Naylor, Stuart Hughes, Tom McCarthy, Sumeet Ambarkhane, Danish Memon, Michael Millward, Sumanta Pal and Ignacio Melero
Cancers 2025, 17(23), 3883; https://doi.org/10.3390/cancers17233883 - 4 Dec 2025
Viewed by 123
Abstract
Renal cell carcinoma (RCC) is a biologically heterogeneous malignancy accounting for 3% of adult cancers globally. Despite advances in immune checkpoint inhibitors (ICIs) and vascular endothelial growth factor (VEGF)-targeted therapies, durable disease control remains elusive for many patients. Increasing evidence implicates the acidic [...] Read more.
Renal cell carcinoma (RCC) is a biologically heterogeneous malignancy accounting for 3% of adult cancers globally. Despite advances in immune checkpoint inhibitors (ICIs) and vascular endothelial growth factor (VEGF)-targeted therapies, durable disease control remains elusive for many patients. Increasing evidence implicates the acidic tumour microenvironment (TME) as a critical mediator of RCC progression, immune evasion, and therapeutic resistance. Solid tumours, including RCC, exhibit reversed pH gradients, characterised by acidic extracellular (pH 6.2–6.9) and alkaline intracellular conditions. This dysregulation arises from enhanced glycolysis, hypoxia-driven lactate accumulation, and the overexpression of pH-regulating enzymes such as carbonic anhydrase (CA9). Acidic TMEs impair cytotoxic T-cell and NK-cell activity, promote tumour-associated macrophage (TAM) polarisation towards an immunosuppressive phenotype, and upregulate alternative immune checkpoints. These mechanisms collectively undermine ICI efficacy and contribute to primary and secondary treatment resistance. Proton-sensing G-protein-coupled receptors (GPCRs), notably GPR65, have emerged as pivotal mediators linking extracellular acidosis to immune dysfunction. Preclinical studies demonstrate that GPR65 antagonists restore anti-tumour immune activity by reversing acidosis-driven immunosuppression and enhancing antigen processing. In RCC models, selective GPR65 inhibitors have shown the ability to reduce immunosuppressive cytokine IL-10 production, induce immunoproteasome activation, and synergise with anti-PD-1 therapy. The first-in-class GPR65 inhibitor, PTT-4256, is now under evaluation in the Phase I/II RAISIC-1 trial (NCT06634849) in solid tumours, including RCC. Targeting acid-sensing pathways represents a novel and promising therapeutic strategy in RCC, aiming to remodel the TME and overcome ICI resistance. Integrating GPR65 inhibition with existing immunotherapies may define the next era of RCC management, warranting continued translational and clinical investigation. Full article
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