Synergy Between Radiopharmaceutical Therapy and Immune Response: Deciphering the Underpinning Mechanisms for Future Actions

Radiopharmaceutical therapy (RPT) has, in comparison to external-beam radiation therapy (EBRT), the unique advantage of addressing all tumor sites, including occult metastases. On the other hand, dose heterogeneity is the Achilles heel of RPT. Tumor-absorbed doses can vary widely between patients and in the same patient (1). Nonhomogeneous target expression also leads to intralesional dose heterogeneity, including in tiny metastases (2). To counter the impact of heterogeneity and maximize tumor cell killing, research in RPT has often investigated the maximum tolerated dose. However, this unavoidably leads to increased toxicity to healthy tissues. For example, lymphocyte decrease in blood was correlated with spleen and bone marrow–absorbed doses from [¹⁷⁷Lu]Lu-DOTATATE (1). The concept of maximum tolerated dose also ignores the synergy that exists between radiation and the immune system, through radiation-induced immunostimulatory effects. In this regard, the use of higher activities might not be necessarily beneficial as it can hamper mounting an immune response, as shown in the article by Constanzo et al. reported in The Journal of Nuclear Medicine (3).

It has long been recognized that radiation stimulates phenotypic changes that modulate the immune susceptibility of tumor cells. This has also raised interest in using radiotherapy to promote greater response to immunotherapies. Preclinical and clinical data have shown that low-dose EBRT can reshape the tumor microenvironment of tumors with scarce immune infiltration and together with immunotherapy induce simultaneous mobilization of innate and adaptive immunity (4). Similar findings have also been reported with RPT (5,6). In one study, combined RPT and immune checkpoint inhibitors (ICI) activated production of proinflammatory cytokines, promoted tumor infiltration and clonal expansion of CD8⁺ T cells, and reduced metastases (5).

Antigen presentation by major histocompatibility complex (MHC) proteins is essential for adaptive immunity. The MHC-I system, also called human leukocyte antigen class I in humans, plays a pivotal role in immune surveillance by presenting processed antigens, including tumor neoantigens, to CD8⁺ T cells. Interaction between a T cell receptor and specific peptide–MHC complexes can trigger T cells to proliferate and mount a specific cellular immune response. One of the recognized effects of EBRT is the increases in cell surface expression of MHC-I molecules, intracellular peptide levels, and antigen presentation, with cytotoxic T lymphocyte recognition of irradiated cells (7). There have been some data showing that RPT could upregulate the expression of MHC-I (8), but these studies were performed in vitro or in immunocompromised animal models.

To investigate the role of MHC-I in RPT, Constanzo et al. used 2 different murine melanoma cell lines that express either low or high MHC-I levels (B16F10 MHC-I-low and B16K1 MHC-I-high) and engrafted them in C57BL/6J syngeneic mice as well as in athymic nude mice (3). The response to a single injection of [²²⁵Ac]Ac-DOTA-TA99 (monoclonal antibody targeting the melanosomal polypeptide TYRP-1/gp75), with 2 different levels of activities (9.25 or 18.5 kBq), was assessed and related to dosimetry (using the distribution of ¹¹¹In-DTPA-TA99 as a surrogate).

Similar antitumor effects and delays in tumor growth were obtained with 4 times lower absorbed dose in melanoma grafts with high MHC-I expression than in melanoma grafts with low MHC-I expression (3). Another key finding is that tumor response to 9.25 kBq of [²²⁵Ac]Ac-DOTA-TA99 was better in C57BL/6J immunocompetent mice than in athymic nude (immunocompromised) mice, suggesting a crucial role of T cell–mediated immune response. Interestingly, increasing the administered activity of α-RPT (18.5 kBq instead of 9.25 kBq) resulted in white blood cell decreases from bone marrow toxicity but did not result in improved tumor control. The authors conclude that MHC-I expression may predict immunostimulatory effects, and that RPT regimens should take into account MHC-I expression level.

For clinical relevance, they examined tissue samples from 12 patients with well-differentiated metastatic thyroid cancer or grade 2 midgut neuroendocrine tumors scheduled for RPT. MHC-I expression varied widely among patients. MHC-I expression correlated with the level of CD8⁺ infiltration (3). It will be interesting to see how these markers correlate with response to RPT and patient outcomes, as the authors are planning to investigate.

As the investigators note MHC-I expression is necessary for CD8⁺ T cell–mediated cytotoxicity. However, many tumors avoid immune surveillance by limiting MHC-I expression, which also leads to resistance to CD8⁺ T cell–based immunotherapies, such as checkpoint blockade (9). Immunogenic stimuli including EBRT or interferon-γ can induce MHC-I expression in many tumor models that have not undergone epigenetic silencing. RPT increased MHC-I in melanoma cells that already strongly expressed MHC-I but was ineffective in MHC-I-low tumors (3). Whether a combination with interferon-γ could be helpful in some instances, as suggested by the authors, warrants investigation.

An important aspect of this study is that relatively low absorbed doses of α-RPT induced surface MHC-I expression (3), whereas this was not seen in a study using low absorbed doses of β-RPT (5). Immune activation through the cyclic guanosine monophosphate–adenosine monophosphate synthase-stimulator of interferon genes (cGAS-STING) pathway has been shown to be an important pathway for β-RPT (5) as well as for α-RPT (6). Differences in immune activation between α- and β-RPT still need to be deciphered.

Due to prolonged blood circulation, radioimmunotherapy has less favorable tumor–to–bone marrow dose ratios than does RPT with small ligands, which might have contributed to the reduced immune response with increased administered activity (3). Limiting systemic lymphodepletion is important. In the context of combination therapy with ICI, lymphodepletion may blunt a systemic immune response (5). Agents that have off-target uptake in immune-rich organs such as the bone marrow, spleen, or lymph nodes may also cause systemic lymphodepletion. Therefore, as future clinical trials combining RPT with ICI are developed, systemic lymphopenia may be an important toxicity to consider during phase I development and dose-finding studies.

The reported findings are important as they suggest that immune response might compensate for a lower absorbed dose (3), thus reducing the impact of dose heterogeneity in RPT (1,2). The study opens new avenues and will stimulate further research. It will be important to understand the mechanisms that initiate and lead to enhanced MHC-I expression. Do these mechanisms depend on DNA damage, cGAS-STING pathways (10), or other radiation pathways (membrane, etc.)? Do they differ with the type of radiation (α, β⁻, Auger), cellular location of the radiopharmaceutical (e.g., intracytoplasmic or membrane), and half-life? Would these mechanisms involve only irradiated cells or also propagate to nonirradiated neighboring and distant cells? With EBRT, it has been shown that extracellular vesicles released from irradiated cells can upregulate MHC-I in nonirradiated tumor cells through activation of the ataxia telangiectasia mutated/ataxia telangiectasia mutated Rad-3 related/checkpoint kinase 1 axis and downstream Janus kinase–signal transducer and activator transcription protein signaling (11). Also, which types of peptides and neoantigens are presented with MHC-I enhancement? Are these peptides tumor-specific, radiation-specific, or both? Although there are some data with EBRT (12), investigations in specific settings of RPT are needed.

With its ability to deliver radiation to disseminated lesions, also stimulating immunogenicity at all disease sites and with various dose levels, RPT might lend itself, better than EBRT, to combination with ICIs. However, despite some encouraging results, many questions remain surrounding the optimal approach to clinical implementation. Understanding the underlying mechanisms will be key. Successful combinations will probably require more personalized RPT approaches with modifications of standard RPT regimens to optimally sustain immune fitness and enhance the antitumor immune response.

Early use of RPT to eradicate occult micrometastases might offer a cure. As absorbed doses in tiny lesions can be low and potentially heterogeneous (2), combination with ICIs could prove synergistic. Investigating this combination in the neoadjuvant setting, where ICIs are displaying high potential, should be encouraged.

We congratulate Constanzo et al. for having brought into light some aspects of the synergy between RPT and immune response, setting the basis for future studies.

• © 2025 by the Society of Nuclear Medicine and Molecular Imaging.

• Received for publication March 4, 2025.
• Accepted for publication March 11, 2025.