Introduction

Lung cancer remains a major global health challenge and the leading cause of cancer-related mortality worldwide. Data from the GLOBOCAN 2020 indicate that it accounted for nearly 1.8 million deaths in 2020, corresponding to approximately 18% of all cancer deaths [1]. Lung cancer is broadly classified histologically into two main entities, non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC). NSCLC accounts for approximately 85% of lung cancer cases, and SCLC, which is a more aggressive neuroendocrine malignancy, comprises about 15% of cases [2].

SCLC is characterized by rapid proliferation, early metastatic spread, initial chemosensitivity, but frequent relapse and poor long-term survival (often less than 7% five-year survival for extensive-stage disease) [3]. NSCLC is a heterogeneous group of tumors that includes the major histologic subtypes of adenocarcinoma and squamous-cell carcinoma. According to the World Health Organization (WHO) classification criteria, adenocarcinoma accounts for roughly 40% of lung cancers, and squamous-cell carcinoma about 30%. Compared with SCLC, NSCLC typically grows more slowly and often presents at a less advanced stage [4].

Therapeutic options for both SCLC and NSCLC have seen significant advances in recent years. NSCLC treatment has been notably enhanced by a range of targeted therapies that inhibit specific driver mutations such as EGFR, ALK, ROS1, MET, and HER2, alongside immune checkpoint inhibitors [5]. Additionally, combined approaches involving chemoradiation and immunotherapy have become standard in many cases, improving patient outcomes [5].

However, despite these advancements, many patients either experience disease progression during or before receiving these therapies or lack identifiable mutations that would allow targeted treatment. Consequently, many patients still lack effective precision medicine options [6].

In nuclear medicine, the paradigm of “theranostics”, combining diagnosis (via imaging) and therapy (via targeted radionuclide delivery), has gained momentum [7, 8]. A targeted radioligand therapy (TRT) agent typically consists of a tumor-targeting ligand, a radionuclide, and a chelator/linker that binds them [9, 10]. With such an approach, one can identify target expression by imaging and then deliver cytotoxic radiation via the same or a similar vector.

Clinical success in other tumor types, most notably well-differentiated neuroendocrine tumors (NETs), including lung carcinoids treated with [¹⁷⁷Lu]Lu-DOTATATE, and prostate cancer managed with [¹⁷⁷Lu]Lu-PSMA-617, has firmly validated the therapeutic concept of TRT [9, 11, 12]. In well-differentiated NETs, peptide receptor radionuclide therapy (PRRT) is an established and highly effective modality, with efficacy closely linked to strong somatostatin receptor (SSTR) expression, as confirmed by [⁶⁸Ga]Ga-DOTATATE positron emission tomography/computed tomography (PET/CT). Across clinical trials and real-world cohorts, PRRT consistently achieves high disease control rates, driven by both objective tumor responses and prolonged stabilization, while also improving progression-free survival (PFS) and providing durable symptom relief [13]. This raises the question: Could TRT also play a meaningful role in both SCLC and NSCLC?

In this systematic review, we evaluate the role of TRTs in both SCLC and NSCLC, summarize their mechanisms, evidence, and discuss clinical and translational challenges and opportunities.

Materials and methods

This review was reported according to the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines [14], and was conducted in accordance with established methodological frameworks for systematic reviews and meta-analyses [15, 16]. The protocol for this systematic review has been registered in the International Prospective Register of Systematic Reviews (PROSPERO); registration number (CRD420251238530) [17]. The completed PRISMA 2020 checklist is provided in Table S1.

Risk of bias and quality assessment

Risk of bias in each clinical study included in the systematic review was assessed using the Risk Of Bias In Non-randomized Studies—of Interventions (ROBINS-I) tool [22]. ROBINS-I evaluates the potential bias across seven domains: (1) bias due to confounding, (2) bias in selection of participants, (3) bias in classification of interventions, (4) bias due to deviations from intended interventions, (5) bias due to missing data, (6) bias in measurement of outcomes and (7) bias in selection of the reported result. Each domain was assessed individually with judgments categorized as low, moderate, serious, critical risk of bias, or no information, depending on the study design. Risk-of-bias assessment was performed independently by two researchers, and any disagreements were resolved through discussion with a third researcher.

For each domain, signaling questions were used to guide the judgment, and the overall risk of bias for each study was determined based on the answers provided. The assessment was conducted using Excel, and Figure 1 was created using RobVis * with an additional reviewer brought in to resolve any potential disagreements between the primary reviewers.

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Figure 1. Risk Of Bias in Non-randomized Studies—of Interventions (ROBINS-I) assessment for included studies.

Results

Study selection

The initial search identified 2,453 published articles, from which 799 duplicates were removed, leaving 1,654 records for screening. Following the title and abstract evaluation, 1,636 studies were excluded as they did not meet the predefined inclusion criteria. During full-text assessment, an additional 3 articles were excluded due to insufficient data. Ultimately, 15 studies were included in the review, comprising 7 prospective clinical trials/prospective cohorts [23–29], 3 retrospective cohorts [30–32], 4 case reports [33–36], and 1 case series [37]. (Figure 2).

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Figure 2. Study selection process illustrated using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 flow diagram. The diagram shows the identification, screening, eligibility, and inclusion steps of the literature search. Adapted from [14]. Accessed Nov 25, 2025. © 2024–2026 the PRISMA Executive. Distributed under a Creative Commons CC BY 4.0 license.

Discussion

To the best of our knowledge, this systematic review is the first to comprehensively synthesize the evolving evidence for TRT across both major histological subtypes of lung cancer, SCLC and NSCLC. Our analysis of fifteen studies [23–37], encompassing 105 patients who received TRT, reveals a rapidly developing field characterized by promising yet preliminary findings. The therapeutic strategies are distinctly bifurcated: PRRT has been the primary focus in SCLC, while emerging research in NSCLC explores FAP and, to a lesser extent, PSMA as novel targets.

Regarding clinical efficacy, PRRT outcomes in SCLC were heterogeneous but demonstrated that disease control may be achievable in a subset of patients. Disease control rates for SSTR-targeted therapy ranged from 0% to 50% across studies [25, 26, 31, 32, 37]. Notably, the most favorable outcomes were reported by Lapa et al. [31], where two of four treated patients achieved prolonged disease stabilization (median PFS 11.9 months) with [¹⁷⁷Lu]Lu-DOTATATE/TOC. In contrast, studies utilizing [⁹⁰Y]Y-based agents uniformly reported 0% disease control and were associated with higher rates of hematologic toxicity [25, 26]. Emerging evidence from alpha-emitter PRRT further supports the theranostic rationale in SCLC; a recent case by Tuncel et al. [36] demonstrated a marked partial metabolic response following a single cycle of [²²⁵Ac]Ac-DOTATATE in a chemotherapy-refractory patient. This suggests that the choice of radionuclide is a critical determinant of both efficacy and safety, with [¹⁷⁷Lu]Lu potentially offering a more favorable therapeutic index in this setting, while alpha-emitter strategies may represent a promising next-generation alternative.

In NSCLC, the emerging data on FAP-targeted therapy are particularly biologically interesting with early signals of activity, albeit based on a very small number of patients. Two case reports using [¹⁷⁷Lu]Lu-FAP-2286 demonstrated partial metabolic responses after a single cycle, indicating potent biological activity [34, 35]. This is supported by the larger mixed-cohort study by Xie et al. [23], where [¹⁷⁷Lu]Lu-FAP-2286 achieved a 44.4% PR rate and a 78% disease control rate in a population of advanced SCLC and NSCLC patients. Conversely, the single case of NSCLC treated with [¹⁷⁷Lu]Lu-PSMA-617 revealed a fundamental pharmacokinetic challenge, with a low tumor-absorbed dose (0.74 Gy/GBq) due to rapid washout, underscoring that target expression on imaging does not always guarantee therapeutic efficacy [33].

Importantly, TRT demonstrated a generally favorable safety profile in lung cancer patients, particularly for [¹⁷⁷Lu]Lu-based agents. Across the included studies, only 3 patients had severe (grade 3/4) toxicities. The most common AEs were mild to moderate hematologic toxicities, which were generally manageable. This favorable tolerability is a significant advantage for heavily pre-treated patients in the salvage or palliative settings where these therapies are currently being applied.

None of the included studies directly compared TRT with standard systemic treatments, underscoring a significant gap in the current research landscape. Moreover, the vast majority of patients in these studies had undergone extensive pretreatment with chemotherapy, immunotherapy, and/or radiotherapy before receiving TRT. Therefore, investigating the efficacy of these novel theranostic approaches in earlier lines of therapy or in selected patient populations with high target expression could offer valuable insights into their potential role in the treatment paradigm.

The predictive value of baseline SSTR-, FAP-, or PSMA-directed PET for subsequent therapeutic efficacy remains an area of active investigation. While SSTR-PET was shown to change management towards PRRT in a majority of SCLC patients in one study [30], and FAP-PET reliably identifies FAP-expressing tumors, their capacity to forecast therapeutic outcomes is multifaceted and not yet fully elucidated. A key challenge, particularly for FAP- and PSMA-targeting agents in NSCLC, is the rapid washout of these compounds from tumor tissues, which can diminish the delivered radiation dose [28, 33]. It is anticipated that baseline PET uptake alone is insufficient to predict TRT efficacy. Tumor retention kinetics, internalization rates, and absorbed doses appear far more critical than qualitative visual assessment or static SUV measurements. A notable finding emerging from this review is the potential value of combining TRT with complementary treatment modalities. In the radioimmunotherapy study by Yu et al. [27], the intratumoral arm of [¹³¹I]Iodine-chTNT, although not included in the present analysis, which focused exclusively on the systemic approach, demonstrated a markedly higher intratumoral response rate (56%) compared with the modest systemic response rate (9.1%). This differential pattern underscores a distinct mechanism of action driven by direct tumoral retention of the antibody construct, suggesting that locoregional delivery may offer synergistic potential when integrated with systemic or multimodal regimens.

Regarding radionuclide selection, our findings in SCLC suggest that [¹⁷⁷Lu]Lu may be preferable to [⁹⁰Y]Y due to its more favorable safety profile and observed instances of efficacy. For novel targets such as FAP-, addressing the challenge of rapid ligand washout is critical for effective radionuclide therapy. Radionuclides with shorter or more compatible half-lives, such as terbium-161 [¹⁶¹Tb]Tb [38], show promise because of their emission characteristics, including beta particles and densely ionizing Auger electrons that can increase tumor cell kill at micro dosimetric levels [38].

Given the extremely limited and heterogeneous evidence base, TRT in lung cancer should currently be regarded as an experimental therapeutic approach. Its use ought to be restricted to prospective clinical trials or, in exceptional circumstances, highly selected salvage cases managed in experienced centers with access to individualized dosimetry, multidisciplinary evaluation, and close post-therapy monitoring. At present, there is no evidence to support the routine or first-line use of TRT in either SCLC or NSCLC outside a research framework.

It is important to indicate that this review has several limitations. First, the number of patients treated with TRT, particularly for NSCLC, is very small, and the evidence is dominated by retrospective cohorts and case reports, which are susceptible to publication bias. Significant variability exists across the included studies, with marked differences in patient populations, therapeutic protocols, radionuclides, and outcome reporting, which complicates the ability to conduct a pooled quantitative analysis. The almost universal application of TRT in a late-line, heavily pretreated setting limits generalizability to earlier disease stages. Consequently, it is imperative to conduct additional prospective studies with larger sample sizes, standardized protocols, and extended follow-up durations to enhance our understanding of the intervention’s efficacy, optimal implementation, and long-term safety in both SCLC and NSCLC.