Radiotherapy and DNA damage-based chemotherapy targeting tumor cells are potential partners of immune checkpoint inhibitors (ICIs) to improve therapeutic efficacy in poor ICI responders [1], [2]. Although the objective response rate of ICI monotherapy is 20–40% in some cases [3], the percentage of patients who can be administered ICI is limited owing to the limited rate of positive biomarkers in patients. Variations in sensitivity are related to differences in the immune status of the tumor microenvironment [4]. In terms of ICI responsiveness, tumors are broadly classified into two types depending on the state of the tumor immune environment. Tumors in which T lymphocytes infiltrate into tumors but are not activated are classified as hot immune tumors. ICI treatment effectively reactivates the anti-tumor immunity in such tumors [4]. By contrast, tumors with little infiltration of T lymphocytes are classified as cold immune tumors, in which ICI treatment shows poor efficacy [4]. Thus, it is important to develop a method to transform cold into hot tumors to maximize the effects of ICI. Ionizing radiation (IR), which predominantly induces DNA double-strand breaks (DSBs), promotes T cell infiltration in tumors and enhances the anti-tumor effect of ICIs, suggesting that radiotherapy has the potential to convert tumor types from cold to hot [5], [6]. In support of this notion, clinical trials have reported that RT in combination with ICI improves therapeutic efficacy compared with ICI therapy alone [7], [8], [9]. However, other groups have reported that combination therapy does not show better outcomes although further assessment of the timing of ICI treatment and the dose of RT is required [10], [11]. To optimize the regimen of RT (or DNA damage-based chemotherapy, hereafter defined as chemotherapy or chemotherapeutic drug) in combination with ICI therapy, further studies are required and also the information from all datasets obtained from basic and clinical studies should be comprehensively analyzed and summarized.

A detailed understanding of the immunological effects of RT in the context of the tumor microenvironment is essential for the rationale of the combination therapy. Accumulating studies have shown that cell surface molecules such as human leukocyte antigen class I (HLA-I), Fas cell surface death receptor, natural-killer group 2, member D receptor, and its ligands are enhanced in response to DNA damage [12], [13], [14], [15], [16]. Following the upregulation of these immunomodulatory ligands, DNA-damaged tumor cells interact with immune cells via their receptor, leading to signal transduction that upregulates the immune responses. In addition, upon DNA damage, cells release damage-associated molecular patterns (DAMPs), such as ATP, high mobility group box protein1 (HMGB1), and calreticulin, which promote immunogenic cell death [17], [18]. Particularly, DAMPs, released after IR, contain double-stranded DNA resulting in the upregulation of the cyclic GMP–AMP synthase (cGAS)/stimulator of interferon genes (STING) pathway when taken up by dendritic cells. This eventually leads to the activation of the interferon (IFN) α/β signaling [19]. DAMPs-induced IFN β production stimulates the activation of cytotoxic T cells via dendritic cells. Although DNA damage-mediated immunostimulatory effects are upregulated, DNA damage also causes immunosuppressive effects. For example, DNA damage promotes transforming growth factor-β signaling, suppressing anti-tumor immunity [20], [21]. This immunosuppressive effect is explained by the induction of cell differentiation into M2-like macrophages, regulatory T cells, and cancer-associated fibroblasts, followed by the secretion of anti-inflammatory cytokines [22]. Furthermore, DNA damage enhances the expression of PD-L1 and the macrophage immune checkpoint molecule CD47 on the surface of tumor cells [23], [24], [25]. Thus, DNA damage causes numerous effects in terms of anti-tumor immunity in the tumor microenvironment; therefore, the final status of the microenvironment depends on the type of tumor, tissue, organ, and the chemoradiotherapy regimen [1], [2], [18]. Nevertheless, the understanding the underlying mechanism is necessary to enable the manipulation of immune activity under the combination of chemoradiotherapy and ICIs. Recently, multiple research groups including ours have demonstrated upregulation of PD-L1 on the cell surface after DNA damage [23], [26], [27]. The upregulation of PD-L1 is also demonstrated in patients after RT [28], [29]. By contrast, HLA-I has not been well studied since the 2000 s, showing that IR upregulates its presentation on the cell membrane and induces the activation of cytotoxic T cells [12]. In this review, we describe how DNA damage enhances HLA-I presentation and activates T cells, based on our recent findings [13].