Safety and toxicity risks of radiotherapy combined with PD-1/PD-L1 inhibitors: A comprehensive review

Abstract

Radiotherapy (RT) combined with PD-1/PD-L1 Inhibitors has demonstrated remarkable efficacy across various cancers. However, concerns remain regarding its safety and potential toxicity. We analyze toxicity risks of RT combined with anti-PD-1/PD-L1 therapy based on current clinical studies. While a slight increase in grade 1-2 pneumonitis has been reported in patients with lung cancer, no consistent evidence suggests a rise in ≥ grade 3 pulmonary toxicity. Additionally, the combination appears well tolerated in the central nervous system, head and neck, and hepatic malignancies. This narrative review investigates key factors that may influence the risk of toxicity in combination therapy, including the dose and fractionation of RT, sequencing with immunotherapy, timing and duration of immune consolidation, and regimen heterogeneity. This review adheres to the SANRA (Scale for the Assessment of Narrative Review Articles) guidelines.

Keywords: Immune response; Oncology; Therapy.

Graphical abstract

Figure 1

Schematic illustration of the immunological mechanisms underlying the combined effect of radiotherapy and PD-1/PD-L1 Inhibitors RT induces immunogenic cell death (ICD), resulting in the release of damage-associated molecular patterns (DAMPs) including HMGB1, calreticulin (CRT), and ATP.^,,,, These signals activate dendritic cells (DCs), leading to antigen cross-presentation and priming of CD⁸⁺ cytotoxic T lymphocytes. Concurrently, RT promotes the accumulation of cytosolic double-stranded DNA (dsDNA), which activates the cyclic GMP–AMP synthase (cGAS)–(STING) pathway. cGAS senses dsDNA and generates cGAMP that activates STING, initiating its translocation to the Golgi apparatus and subsequent recruitment of TANK-binding kinase 1 (TBK1) and IκB kinase (IKK). This activation phosphorylates IRF3 and NF-κB, leading to the production of type I interferons (e.g., IFN-β) and pro-inflammatory cytokines (e.g., IL-1β, IL-6, TNF-α), thereby promoting a pro-immunogenic TME.^, cGAS–STING signaling reshapes the TME by depleting regulatory T cells (Tregs), reprogramming tumor-associated macrophages (TAMs) toward an M1-like phenotype, and suppressing the immunosuppressive activity of myeloid-derived suppressor cells (MDSCs). Cancer-associated fibroblasts (CAFs) also respond to IFN-I and inflammatory signals by secreting chemokines that facilitate immune cell recruitment. CD4⁺ T cells are polarized toward effector phenotypes that sustain adaptive immunity. However, the activation of the STING–TBK1–IRF3 axis can also upregulate PD-L1 expression on tumor cells, leading to T cell exhaustion and adaptive immune resistance. PD-1 or PD-L1 antibodies restore T cell effector function, reduce MDSC accumulation, and synergize with RT-induced immune activation, resulting in enhanced and durable anti-tumor responses. Acute activation of cGAS–STING promotes antitumor immunity, whereas prolonged signaling may induce immune dysregulation and toxicity. Chronic stimulation of cGAS–STING following RT can induce the secretion of immunosuppressive cytokines such as interleukin-10 (IL-10) and transforming growth factor β (TGF-β), which facilitate the recruitment of myeloid-derived suppressor cells (MDSCs) and Tregs 5.^, This immunosuppressive shift, paradoxically coupled with localized inflammation, may promote immune tolerance while aggravating collateral tissue damage. Within the irradiated TME, cGAS–STING activation upregulates pro-inflammatory phenotypes in CD4⁺ T cells,^, cancer-associated fibroblasts (CAFs), and macrophages.^,, CD4⁺ T cells release cytokines such as IL-2 and IFN-γ that amplify immune cascades, while macrophages undergo M1 polarization and secrete TNF-α and IL-6^,. Concurrently, CAFs also release chemokines such as CXCL12, amplifying the inflammatory response. Although this immune amplification enhances tumor clearance, it can also pose substantial risk to surrounding normal tissues. Created inhttps://BioRender.com.

Figure 2

Schematic illustration of immunotoxicity mechanisms induced by combined radiotherapy and PD-1/PD-L1 inhibitors across multiple organ systems Combined radiotherapy and immune checkpoint inhibition may lead to a spectrum of immune-related adverse events involving multiple organs. Lymphopenia and anemia: Inflammatory cytokines and radiation-induced bone marrow suppression impair hematopoietic function, leading to a decrease in blood cells. Dysphagia: Activation of cancer-associated fibroblasts (CAFs) and CD4⁺ T cells in the local mucosa triggers the release of pro-inflammatory cytokines, resulting in mucosal edema and tissue damage. Cutaneous rash: Elevated type I interferons (IFN-I) and T cell cross-reactivity to skin-specific antigens contribute to dermatologic toxicity. Pneumonitis: DNA damage and inflammatory cytokines promote the infiltration of immune cells (such as T cells) into the lung parenchyma, leading to collagen deposition and fibrotic remodeling, which may progress to pneumonia. Gastrointestinal toxicity: Local immune activation disrupts intestinal microbial homeostasis and compromises mucosal integrity, resulting in symptoms such as nausea and diarrhea.^,, Cardiotoxicity: Release of DAMPs and cytotoxic T cell responses against cardiac autoantigens, such as myosin, may trigger myocarditis, arrhythmias, and fibrosis. Neurotoxicity: Type I interferons and pro-inflammatory mediators crossing the blood–brain barrier (BBB) activate glial cells and contribute to neuroinflammation, potentially manifesting as fatigue, cognitive dysfunction, or encephalopathy. Hepatotoxicity: Activated CD8⁺ and CD4⁺ T cells recognize hepatocyte-associated antigens, leading to immune-mediated liver injury.^,Created inhttps://BioRender.com.

Figure 3

Key determinants and mitigation strategies for toxicity in combined radiotherapy and PD-1/PD-L1 inhibitor therapy Key factors influencing toxicity risk when combining radiotherapy with PD-1/PD-L1 inhibition are illustrated. Factors include RT fractionation regimen, timing of RT and PD-1/PD-L1 inhibitions, interval between RT and PD-1/PD-L1 inhibitions initiation, duration of PD-1/PD-L1 therapy, multimodal combination strategies, and tumor/patient baseline characteristics. Personalized treatment planning based on these factors may help reduce toxicity while maintaining therapeutic efficacy.