Clinical Evidence of Combining Radiopharmaceutical Therapy With Immune Checkpoint Inhibitors

Abstract

Radiopharmaceutical therapy (RPT) and immune checkpoint inhibitors (ICIs) represent transformative approaches in treating metastatic cancers. RPT uniquely delivers targeted radiation to primary and metastatic tumors, modulating the tumor microenvironment (TME) to enhance antitumor immunity. The therapeutic advantages of combining RPT with ICI have been shown preclinically. Clinical trials are now emerging, offering insights into the potential therapeutic synergy between RPT and ICI. This review highlights clinical trials of RPT combined with ICI, emphasizing their ability to improve metastatic cancer outcomes while addressing challenges such as toxicity, immunosuppressive TME, and logistical barriers, and underscores their promise to redefine cancer care.

Introduction

Metastatic disease accounts for approximately 90% of cancer-related deaths^1–6. Unfortunately, effective therapeutic strategies remain limited despite tremendous advances in cancer research⁷. Radiopharmaceutical therapy (RPT) represents a groundbreaking approach to treating metastatic disease by delivering targeted radiation to tumors throughout the body ^8,9. Leveraging pharmaceuticals that selectively bind to cancer cells or accumulate through physiological mechanisms, RPT provides a precise and effective treatment modality. Remarkably, RPT has demonstrated significant therapeutic efficacy with minimal toxicity in several cancer types⁸. As the role of RPT in the management of metastatic disease is on the rise, its combination with immune checkpoint inhibitors (ICIs) holds the potential to enhance clinical responses beyond what is achievable by either monotherapy alone.

For over a century, radiotherapy, including external beam radiation therapy (EBRT) and RPT, has shown dual benefits: tumor eradication and immune activation¹⁰. Radiation triggers cancer cells to release damage-associated molecular patterns (DAMPs), activating the cGAS-STING pathway, which induces type I interferons and the release of cytokines that recruit immune cells^11,12. The growing promise of RPT in treating metastatic cancer, coupled with emerging insights into the immunogenic effects of radiation, has spurred preclinical and clinical studies exploring the combination of RPT and immunotherapy, such as ICIs. This review explores clinical trials investigating the combination of RPT with ICI, highlighting key clinical findings, potential challenges, and future directions in this emerging field.

1-. Radiopharmaceutical therapy (RPT)

RPT has emerged as a promising systemic therapy, enabling radiation delivery to both local and metastatic lesions while sparing healthy tissues (Fig. 1A)^8,13. Unlike EBRT, which delivers radiation to all tissues in the radiation field, including malignant and adjacent normal tissues, RPT uses tumor-targeting biomolecules (e.g., antibodies, peptides, or small molecules) linked to a radionuclide to form a “radiopharmaceutical” that preferentially targets cancer cells (Fig. 1B). The radiopharmaceutical binds selectively to receptors overexpressed on tumor cells, thus delivering radiation to the tumor while minimizing damage to surrounding tissues¹⁴. This molecularly-targeted approach makes RPT particularly effective for treating metastatic and microscopic tumors^8,15–17, where EBRT’s utility is often limited. The efficacy of RPT depends on the targeting molecule’s properties, the radionuclide’s physical characteristics, and the tumor characteristics such as receptor expression, size, and tumor type. Additional factors, such as the administrated activity, tumor uptake, and pharmacokinetics, also impact the treatment outcome¹⁸. As such, carefully considering these factors is crucial for RPT’s clinical efficacy and safety. The approvals of several radiopharmaceuticals, such as [²²³Ra]Ra-dichloride (Xofigo®) and [¹⁷⁷Lu]Lu-PSMA-167 (Pluvicto®) for metastatic castration-resistant prostate cancer (mCRPC), and [¹⁷⁷Lu]Lu-DOTATATE (Lutathera®) for gastroenteropancreatic neuroendocrine tumors (GEP-NET) have sparked a new excitement in the field ^19–21. RPT faces challenges like suboptimal targeting, radioresistance, and limited immune stimulation, hindering tumor eradication^22–24. Combining RPT with systemic therapies, such as ICIs, may overcome these limitations and improve outcomes.

Figure 1:

Radiopharmaceutical therapy delivers systemic radiation to tumor. A) A radiolabeled, tumor-specific compound known as a “radiopharmaceutical” is administered intravenously resulting in selective accumulation of radionuclide in the tumor microenvironment (TME). B) Pharmacophoric model of radiopharmaceutical agent. A targeting molecule is conjugated to a therapeutic radionuclide via a linker and chelator, forming a radiopharmaceutical that ensures precise delivery of radiation to tumor cells.

1.1-. Targeting molecules

In RPT, targeting molecules such as antibodies, peptides, or small molecules are designed to bind selectively to tumor-specific receptors or antigens, ensuring precise delivery of radiation to cancer cells while sparing healthy tissues²⁵.

- Antibodies:

Their high specificity and potentially strong binding affinity make them ideal for targeting tumor-associated antigens and delivering radiation to cancer cells^26,27. Effective antibodies target highly expressed antigens on tumors but minimally expressed or absent in healthy tissues. However, antibody size can limit tumor microenvironment (TME) penetration²⁸ and prolong circulation²⁹, increasing off-target toxicities. Smaller monoclonal antibody (mAb) fragments like single-chain variable fragments (scFv) partially retain target binding capacity while improving TME penetration. Food and Drug Administration/European Medical Agency (FDA/EMA)-approved examples of antibody-based radiopharmaceuticals include Zevalin® ([⁹⁰Y]Y-ibritumomab tiuxetan)³⁰ and Bexxar® ([¹³¹I]I-tositumomab)³¹, which target the CD20 protein on the surface of B-cells expressed by non-Hodgkin lymphoma.

- Peptides:

They are versatile for RPT due to rapid TME penetration, high uptake, and quick clearance from non-target tissues, offering optimized pharmacokinetics. Their relatively higher stability enables chemical modifications and radiolabeling, making them versatile agents in nuclear medicine. A notable example of peptide-based FDA/EMA-approved radiopharmaceutical is Lutathera® ([¹⁷⁷Lu]Lu-DOTA-TATE), indicated for the treatment of somatostatin receptor 2 (SSTR2)-positive gastroenteropancreatic neuroendocrine tumors^32,33.

- Small molecules:

Small molecule-based radioligands offer advantages as radiopharmaceuticals due to their efficient TME penetration and rapid clearance from systemic circulation, reducing off-target effects and toxicity. Although less specific than antibodies or peptides, small molecules effectively target cancer-associated antigens, such as the prostate-specific membrane antigen (PSMA) in prostate cancer. A notable example is the FDA-approved [¹⁷⁷Lu]Lu-PSMA-167 (Pluvicto®) for mCRPC³⁴, showcasing the potential of radioligand therapy in precision oncology.

Each targeting molecule in RPT offers a unique balance of strengths and limitations, with selection guided by tumor traits, precision, clearance, and off-target risks. This enables personalized and effective cancer therapy.

1.2-. Radionuclides

A wide range of radionuclides is available for RPT, and selecting the appropriate one is crucial, as it directly influences treatment safety and efficacy. This choice is guided by factors such as physical half-life, availability, cost, radiochemical methods, and radiation properties, including energy level, type (alpha, beta, or Auger electrons), linear energy transfer (LET), and penetration range (Fig. 2 and Table 1).

Figure 2:

Characteristics of various radionuclides used for radiopharmaceutical therapy.

Table 1:

Radionuclides used in RPT and their physical properties

Particle emitted	Energy	Range	LET	Key DNA Damage characteristics	Example of Radionuclide
β-particles	0 – 2.3 MeV	Up to cm	0.2 keV/μm	Mostly single-strand breaks and some double-strand breaks easily repairable (Lower lethal damage efficiency)	131I, 90Y, 177Lu
α-particles	5 – 9 MeV	50 – 100 μm	50 – 230 keV/μm	Mostly clustered double-strand breaks, making them complex and difficult to repair. (Higher lethal damage efficiency)	225Ac, 211At, 223Ra
Auger and conversion electrons	< 1 keV	< 1 μm	4 – 26 keV/μm	Mix of Clustered double-strand breaks and single-strand breaks (Lethality dependent on nuclear DNA proximity)	123I, 125I, 195mPt, 111In

The physical half-life:

The time needed for half of its radioactive atoms to decay is critical in RPT. It must be amenable to the radiolabelling process, the distribution logistics of the agent, and the targeting molecule’s pharmacokinetics. While radionuclides with a short half-life, measured in hours, are preferred for imaging application, PRTs featuring short T1/2 radionuclides may lead to significant decay before the radiopharmaceutical reaches the TME, thus reducing treatment efficacy. Conversely, a long half-life can increase radiation exposure to healthy tissues, thus increasing treatment-related side effects. Ideally, RPT radionuclides should have a half-life of 1 to 7 days for optimal balance³⁵.

Linear Energy Transfer (LET):

The energy deposited by ionizing radiation per unit distance in tissue (keV/μm) significantly influences its biological effect. High-LET radiation (e.g., alpha particles, 50–230 keV/μm) induces dense clusters of double-strand DNA breaks (DSBs), causing irreparable DNA damage and high cytotoxicity. Intermediate-LET radiation (e.g., Auger electrons, 4–26 keV/μm) generates localized single-strand DNA breaks (SSBs) and DSBs, with cytotoxicity dependent on nuclear proximity due to limited penetration. Low-LET radiation (e.g., beta particles, 0.2 keV/μm) primarily induces SSBs and indirect damage via free radicals, which are often repairable, though clustered SSBs may result in DSBs^36,37. Radionuclides used in RPT are classified into three main categories based on their radiation type: beta (β) particle emitters, alpha (α) particle emitters, and Auger/conversion electrons emitters.

β-particle emitters, including Lutetium-177 (¹⁷⁷Lu), Yttrium-90 (⁹⁰Y), and Iodine-131 (¹³¹I), with a low LET (~0.2 keV/μm) and tissue penetration up to 12 mm, have been widely used in RPT. Due to their deeper penetration range (several millimeters), low-LET β⁻-emitters can effectively treat heterogeneous (target expression) tumors^38,39, resulting in more effective tumor coverage^40,41, but may have lower lethal damage efficiency per unit dose.

α-particle emitters like Radium-223 (²²³Ra) and Actinium-225 (²²⁵Ac), deliver potent therapy with high LET (50 – 230 keV/μm) and a short tissue range (50–100 μm), thus ideal for micrometastases^39,40,42. Their high LET causes dense clusters of DSBs, which are difficult to repair³⁹, making them highly cytotoxic⁴³.

Auger/conversion electron emitters such as Iodine-123 (¹²³I), Iodine-125 (¹²⁵I), and Indium-111 (¹¹¹In), have a very short tissue range (<1 μm), making them effective near critical cell structures like nuclear DNA, and medium-to-high LET (4 – 26 keV/μm) inducing a mix of SSBs and DSBs^16,39,42.

Many β-particle and Auger emitters also emit γ rays, enabling their dual use for therapy and imaging⁴⁴. For example, γ emissions from ¹⁷⁷Lu allow real-time visualization of radiopharmaceutical distribution, ensuring accurate targeting and dose optimization^45,46.

Overall, radionuclide selection for RPT depends on properties like half-life, LET, radiation type, and tissue penetration. β-emitters appear to be better suited for larger tumors, while α-emitters target micrometastases with high cytotoxicity, and Auger emitters provide precise, localized radiation (<1 μm) near critical structures like nuclear DNA.

2-. Immunomodulatory effects of RPT and rationale for combining RPT with ICI

The efficacy of RPT extends beyond direct cytotoxicity, as it induces significant pro-inflammatory immune responses^47,48. Ionizing radiation enhances tumor immunogenicity, modulates the TME, and promotes both innate and adaptive immunity^47,48. Irradiated tumor cells release DAMPs⁴⁹ and express immunomodulatory molecules, recruiting antigenpresenting cells to activate T-cells and drive systemic anti-tumor immunity⁵⁰. Potluri et al. showed that [⁹⁰Y]Y-NM600 modified the TME by increasing CD8+ T cell infiltration, and PD-L1 expression on myeloid cells⁵¹. In a murine study, Hernandez et al. observed a reduction in immunosuppressive regulatory T cells and a notable increase in activated CD8+ T cells in EL4 murine tumors treated with [⁹⁰Y]Y-NM600 compared to controls⁵². Furthermore, upon rechallenging [⁹⁰Y]Y-NM600-treated complete responders with EL4 cells, none developed tumors ⁵², suggesting the induction of a tumor-specific memory in RPT-treated mice. Emerging preclinical data suggest that targeted α-particle therapy (TAT) can also induce immunostimulatory effects⁵³. Lejeune et al. further demonstrated that TAT triggers transcriptional and molecular signatures consistent with immunogenic cell death (ICD) in preclinical syngeneic tumor models⁵⁴. Despite the reported immunomodulatory effects of RPT, its efficacy as a monotherapy often lacks durability, underscoring the compelling rationale for combining RPT with immunotherapy⁵⁵. Foundational studies have shown the synergism between RPT and immunotherapy, such as improved survival with [⁹⁰Y]-anti-CEA (Carcinoembryonic antigen) antibodies in combination with a CEA/TRICOM (TRICOM: three T-cell costimulatory molecules B7-1, ICAM-1, and LFA-3) vaccine in colon cancer models⁵⁶. This combination represents a promising strategy for achieving durable tumor control, so it may pave the way for enhancing patient outcomes through synergistic treatment strategies.

3-. Clinical trials combining RPT with ICI

Building on preclinical evidence, several clinical trials have been initiated to evaluate the safety and efficacy of RPT-ICI combinations across cancers. Key outcomes are discussed here, underscoring the potential of these combination therapies to advance clinical treatment paradigms. Table 2 concisely summarizes these clinical trials, categorized by disease type for clarity.

Table 2:

Selected Clinical Trials Evaluating RPT Combined with Immune Checkpoint Blockade in Cancer.

Disease	Trial	Phase	Disease status	Target	RPT	ICI	Combination sequence	Trial Status/Result	Reference
Prostate Cancer	NCT02814669	Ib	mCRPC	Bone metastases	[223Ra]Ra: 55 kBq/kg (IV) every 28 days, 6 administrations	Atezolizumab: 840 mg (IV) every 14 days	Concurrent or stagerred	Combination: greater toxicity	[57]
	NCT03093428	II	mCRPC	Bone metastases	[223Ra]Ra: every 4 weeks at a predetermined dose (IV)	Pembrolizumab: every 3 weeks at a predetermined dose (IV)	Concurrent	No improved efficacy	[58]
	NCT03658447 (PRINCE)	I	mCRPC	PSMA	[177Lu]Lu-PSMA-617: 8.5 GBq (IV), every 6 weeks, up to 6 cycles	Pembrolizumab: 200 mg every 3 weeks (IV)	Concurrent	PSA-RR: 76% No safety concerns rPFS: 11.2 months PSA-PFS: 8.2 months OS: 17.8 months	[59]
Lung Cancer	NCT03325816	I/II	Extensive stage SCLC	SSTR	[177Lu]Lu-DOTA0-Tyr3-Octreotate: 3.7 or 7.4 GBq (IV), every 8 weeks, 4 cycles	Nivolumab: 240 mg every 2 weeks (IV)	Concurrent	Combination well tolerated PR: 1 out 7 patients	[61]
	NCT03996473	I	Metastatic NSCLC	Bone metastases	[223Ra]Ra: 55 kBq/kg (IV), every 6 weeks, up to 6 cycles	Pembrolizumab: 200 mg every 3 weeks (IV) up to 35 doses	Concurrent	Study closed
Renal Cancer (ccRCC)	NCT05663710	Ib/II	Advanced ccRCC	CAIX	[177Lu]Lu-girentuximab: 1.48 GBq/m2 (IV), every 12 weeks, up to 3 cycles	Nivolumab (dose not available) Cabozantinib: given orally	Concurrent	Ongoing	[62]
	NCT05239533 (STARLITE 2)	II	Advanced ccRCC	CAIX	[177Lu]Lu-girentuximab: 1.8 or 2.4 GBq/m2 (IV), every 12-14 weeks, up to 3 cycles	Nivolumab: 200 mg every 2 weeks	Concurrent	Ongoing	[63]
Merkel Cell cancer	NCT05583708	II	Metastatic	SSTR	[177Lu]Lu-DOTATATE: 7.4 GBq (IV), every 2 months, up to 4 doses	Pembrolizumab: 400 mg every 6 weeks (IV)	Concurrent	Temporarily suspended
	NCT04261855 (GoTHAM)	Ib/II	Metastatic	SSTR	[177Lu]Lu-DOTATATE: two administrations separated by 8- 10 weeks	Avelumab: 10 mg/kg every 2 weeks for 24 months (IV)	Concurrent	Ongoing
Thyroid cancer	NCT03215095	I	Recurrent/Metastatic	rhTSH	[131I]I : 100 mCi	Durvalumab: 1500 mg IV evey 4 weeks	Concurrent	Active, not recruiting
Refractory neuroblastoma	NCT02914405 (MiNivAN)	I	Relapsed or refractory High risk	Norepinephrine Transporter	[131I]I-meta-iodobenzylguanidine (MIBG)	Nivolumab: 3 mg/kg Dinutuximab (Anti-GD2 monoclonal antibody): 50 or 100 mg/m2	Concurrent	Recruiting
NETs with liver metastases	NCT03457948	II	Metastatic	SSTR	[177Lu]Lu-DOTA0-Tyr3-Octreotate	Pembrolizumab	Concurrent	Recruiting

ccRCC: clear cell renal cell carcinoma; IV: intravenous injection; mCRPC: metastatic castration-resistant prostate cancer; NET: Neuroendocrine tumor; NSCLC: non-small cell lung cancer; OS: overall survival; PR: partial response; PSA-PFS: prostate-specific antigen progression-free survival; PSA-RR: PSA response rate (≥ 50% decrease in PSA level); PSMA: prostate-specific membrane antigen; rhTSH: Recombinant human thyroid stimulating hormone; rPFS: radiographic progression-free survival; SCLC: small cell lung cancer; SSTR: Somatostatin Receptor

Prostate cancer

A Phase Ib study (NCT02814669) investigated the combination of [²²³Ra]RaCl₂ with atezolizumab in mCRPC patients with bone, lymph node, or visceral metastases. This combination resulted in greater toxicity than either agent alone and failed to show clinical benefit⁵⁷. Among the grade 3/4 adverse events, 34.1% were attributed to atezolizumab, while 27.3% were associated with [²²³Ra]RaCl₂.

A randomized Phase II study (NCT03093428) evaluated the combination of [²²³Ra]RaCl₂ with pembrolizumab in patients with mCRPC. A recent report showed a median (progression-free survival) PFS of 6.1 months for [²²³Ra]RaCl₂ + pembrolizumab versus 5.7 months for [²²³Ra]RaCl₂ alone and a median overall survival (OS) of 16.9 months versus 16.0 months, respectively⁵⁸. While the combination was well tolerated with no unexpected toxicity, it did not demonstrate improved efficacy.

PRINCE (NCT03658447), a Phase I clinical trial, evaluated the safety and efficacy of [¹⁷⁷Lu]Lu-PSMA-617 in combination with pembrolizumab in patients with mCRPC. The prostate-specific antigen response rate (PSA-RR) was 76% compared to 46% with [¹⁷⁷Lu]Lu-PSMA-617 alone. The median radiographic PFS (rPFS), PSA-PFS, and OS were 11.2 months, 8.2 months, and 17.8 months, respectively⁵⁹. No additional safety concerns were identified with the addition of pembrolizumab, confirming the favorable safety profile of this combination.

Lung cancer

Advanced lung cancer has also been the focus of clinical trials exploring the combination of RPT with immunotherapy. A Phase I/II trial (NCT03325816) investigating the combination of nivolumab and Lutathera in patients with extensive-stage small cell lung cancer (SCLC) demonstrated a tolerable toxicity profile. Lutathera, a beta-emitting [¹⁷⁷Lu]Lu-labeled somatostatin analog approved for gastroenteropancreatic neuroendocrine tumors (GEP-NETs)⁶⁰, targets somatostatin receptor-expressing cells. The combination therapy was well tolerated. Furthermore, one out of seven patients achieved a partial response (PR), while two with pulmonary atypical carcinoid maintained stable disease (SD) for six months. Notably, the patient with PR exhibited the highest tumor uptake of ⁶⁸Ga-DOTATATE on PET/CT, underscoring the potential of this approach⁶¹.

A Phase I study (NCT03996473) sought to evaluate the safety and efficacy of combining [²²³Ra]RaCl₂ with pembrolizumab in metastatic non-small cell lung cancer (NSCLC). The trial included patients who were either treatment-naïve for advanced disease or had progressed after prior PD-1/PD-L1 checkpoint blockade. The primary objectives were assessing tumor shrinkage, duration, and treatment safety. However, the study was closed early due to insufficient accrual.

Renal cancer

Clear cell renal cell carcinoma (ccRCC) is characterized by carbonic anhydrase IX (CAIX) expression due to von Hippel-Lindau (VHL) loss, representing a compelling target for RPT-based therapies. The integration of RPT with immunotherapy in advanced ccRCC is gaining momentum, with two Phase II clinical trials currently underway (NCT05239533; NCT05663710). These trials aim to evaluate the safety and efficacy of combining [¹⁷⁷Lu]Lu-girentuximab with nivolumab as a novel treatment strategy for advanced ccRCC^62,63.

Merkel Cell Carcinoma

Two case reports underscore the significant therapeutic potential of combining RPT with ICI in metastatic Merkel cell carcinoma (MCC). These cases involved patients who had progressed on first-line avelumab or second-line therapies combining ipilimumab, nivolumab, and EBRT^64,65. While up to half of MCC patients may not respond to or develop resistance to ICIs⁶⁵, the frequent expression of somatostatin receptors in MCC makes it a suitable target for [¹⁷⁷Lu]Lu-DOTATATE. In one case, a patient with extensive MCC metastases treated with [¹⁷⁷Lu]Lu-DOTATATE and anti–PD-L1 therapy demonstrated a rapid response, achieving a near-complete response within a month⁶⁴. Another patient receiving [¹⁷⁷Lu]Lu-DOTATOC in combination with ipilimumab and nivolumab achieved a PR that was sustained for five months⁶⁵. Clinical trials (NCT05583708; NCT04261855) have been initiated to evaluate [¹⁷⁷Lu]Lu-DOTATATE combined with nivolumab or pembrolizumab in patients with metastatic MCC.

Other ongoing clinical trials are exploring the combination of RPT with ICI, including radioiodine (¹³¹I) with Durvalumab (NCT03215095) for thyroid cancer, ¹³¹I-MIBG with Nivolumab and dinutuximab (anti-GD2 monoclonal antibody) for refractory neuroblastoma (NCT02914405), and ¹⁷⁷Lu-DOTA0-Tyr3-Octreotate with Pembrolizumab (NCT03457948) for NETs with liver metastases.

Challenges and Future Perspectives

The combination of RPT with immunotherapy is a promising therapeutic option for metastatic cancers. RPT’s targeted radiation delivery and ability to modulate the TME can complement the systemic anti-tumor effects of immunotherapy. Preclinical studies highlight the potential of RPT and ICI combination^47–54, but robust clinical evidence remains limited. Nevertheless, few studies have shown promising results, including case reports with [¹⁷⁷Lu]Lu-DOTATATE or [¹⁷⁷Lu]Lu-DOTATOC plus ICI in MCC metastases^64,65, and the phase I PRINCE trial with [¹⁷⁷Lu]Lu-PSMA-617 in combination with ICI in mCRPC⁵⁹. Beyond these aforementioned studies, we are awaiting results from ongoing clinical trials (See Table 2). Despite these potential benefits, challenges persist, including increased toxicities⁵⁷ with immune-related events and radiation-induced toxicities. The immunosuppressive TME, influenced by regulatory T cells and immune checkpoint expression, may further dampen the treatment efficacy. Variability in patient responses, driven by tumor heterogeneity, highlights the need for predictive biomarkers for optimal patient selection. Economic and logistical barriers also hinder implementation^66–70. RPT production and administration require specialized infrastructure and expertise, while high costs necessitate cost-benefit analyses for integration into clinical practice. Future research should optimize trial designs for sequencing, dosing, and timing of RPT-ICI combinations. Advances in imaging, dosimetry, and collaboration among specialists, along with efforts to reduce costs and improve access, will be key to transforming metastatic cancer treatment. Moreover, most trials do not clearly differentiate whether observed toxicities stem from immune-related effects or radiation exposure. Gaining a deeper understanding of the predominant mechanism, whether immune-mediated or radiation-induced, will be essential for optimizing toxicity management and improving the safety profile of these combinations.

Conclusion

The combination of RPT and immunotherapy offers a transformative approach to metastatic cancer, overcoming current treatment limitations. As shown in Figure 3, RPT synergizes with immunotherapy, including ICIs by reducing tumor burden, releasing neo-antigens, enhancing MHC-I expression, and modifying the TME, while immunotherapy amplifies and sustains these effects, countering immune evasion and optimizing tumor control, especially in “cold” tumors. Despite challenges such as toxicity and logistical barriers, advances in radiopharmaceutical design, immune modulation, and personalized biomarkers driven by interdisciplinary collaboration could redefine cancer care for advanced, treatment-resistant, and metastatic malignancies.

Figure 3:

Potential synergistic interactions between radiopharmaceutical therapy and immune checkpoint inhibitors.