(chemo)radiotherapy

Overview

(Chemo)radiotherapy — encompassing both radiotherapy (RT) alone and chemoradiotherapy (CRT), in which ionizing radiation is combined with systemic chemotherapeutic agents — represents one of the foundational pillars of modern oncological treatment. Radiotherapy leverages high-energy ionizing radiation to induce DNA double-strand breaks, disrupt cellular replication, and drive tumor cell death, while the concurrent or sequential addition of chemotherapy agents (chemoradiotherapy) exploits pharmacological radiosensitization to enhance tumor cell kill beyond what either modality achieves independently. The biological rationale for combining these modalities includes spatial cooperation (chemotherapy targeting distant micrometastases while radiation controls the locoregional disease), temporal cooperation (chemotherapy sensitizing cells to radiation-induced damage), and the exploitation of complementary mechanisms of DNA damage and repair inhibition. (Chemo)radiotherapy is applied across an exceptionally broad range of malignancies — including head and neck cancers, esophageal squamous cell carcinoma, cervical cancer, diffuse intrinsic pontine glioma, rectal cancer, breast cancer, and prostate cancer — where it functions as a definitive, neoadjuvant, adjuvant, or palliative treatment depending on disease stage and patient factors.

The efficacy of (chemo)radiotherapy is governed by complex tumor biology, including the capacity of cancer cells to repair radiation-induced DNA damage via pathways such as homologous recombination (HR) and the Shieldin complex, the oxygenation status of the tumor microenvironment, and the molecular landscape of the tumor. Resistance to radiotherapy — radioresistance — remains a critical clinical challenge and is an active focus of translational research, with investigators identifying specific molecular targets such as EZH2, Pol θ (theta), and mitochondrial RNA polymerase as candidate vulnerabilities. Parallel efforts focus on radiosensitization strategies employing small molecules, natural compounds, nanoparticle delivery systems, and emerging physical modalities such as hyperthermia patches.

Focus of Latest Publications

Recent research has explored radiotherapy approaches across multiple cancer types, with emphasis on optimizing patient selection and treatment sequencing. In early nodal breast cancer, a prospective registry study (RAPCHEM) examined radiotherapy tailored to nodal response after primary chemotherapy, demonstrating excellent locoregional control and providing updated 10-year follow-up data. For older women with stage I hormone receptor-positive breast cancer, the role and necessity of postoperative radiotherapy continues to be investigated as clinicians weigh competing evidence on treatment efficacy.

Advanced radiotherapy modalities and combination strategies are expanding treatment options beyond conventional photon therapy. Proton beam therapy (PBT) has emerged as an alternative to conventional photon therapy for locally advanced pancreatic cancer, evaluated in combination with chemotherapy. Novel combination approaches include hyperthermia-enhanced radiotherapy, where stretchable hyperthermia patches demonstrated substantial synergy with radiotherapy in nasopharyngeal carcinoma, reducing clonogenic cell survival by over 54%, elevating apoptosis by 90%, and enhancing tumor control in vivo. Additionally, immuno-oncology combinations are being investigated, including neoadjuvant tislelizumab (anti-PD-L1 monoclonal antibody) plus chemoradiotherapy for resectable esophageal squamous cell carcinoma, and anlotinib combined with radiotherapy for glioblastoma, particularly in patients with unmethylated MGMT who derive minimal benefit from standard temozolomide chemoradiotherapy.

Understanding and overcoming resistance mechanisms is critical for improving radiotherapy efficacy. Mechanistic studies in cholangiocarcinoma revealed that H3K4 methylation-driven upregulation of Calbindin 2 (CALB2) promotes both immune evasion and chemoradiotherapy resistance through a signaling axis involving Keratin 7 (KRT7) and PD-L1 that impairs T cell activation. CALB2 silencing significantly sensitized cholangiocarcinoma tumors to gemcitabine plus radiotherapy, suggesting that targeting this epigenetic mechanism may overcome resistance to combined modality therapy.

Emerging preclinical models are advancing our capacity to predict radiotherapy response and study tumor microenvironment interactions. Complex cerebral organoids incorporating vasculature and microglial cells successfully modeled glioblastoma behavior and radiotherapy response, demonstrating vascular co-option and reprogramming of microglia into tumor-associated macrophages, with analysis of tumor recurrence following radiotherapy. Such models provide platforms to investigate mechanisms of therapy resistance and inform development of more effective therapeutic strategies.