Antibody-Drug Conjugates in Breast Cancer: Therapeutic-Window Engineering, Tumor Heterogeneity, and Immunotherapy Combinations

Abstract

Antibody–drug conjugates (ADCs) have become a major therapeutic class in breast cancer, but their clinical performance cannot be predicted by antigen expression alone. This review uses therapeutic-window engineering as a unifying framework to connect ADC molecular architecture with tumor heterogeneity, clinical positioning, resistance, immune effects, and toxicity. We examine how target selection, antibody properties, linker stability, payload mechanism and membrane permeability, drug-to-antibody ratio (DAR), conjugation homogeneity, and intratumoral delivery jointly determine efficacy and safety. We then distinguish established clinical uses from investigational strategies across HER2-positive, HER2-low/ultralow, hormone receptor-positive/HER2-negative, and triple-negative breast cancer, reflecting the rapid movement of ADCs into earlier treatment lines and selected early-stage settings. Rather than treating ADCs as a homogeneous class, we critically assess how payload class, linker behavior, bystander killing, Fc-mediated activity, and baseline immune context may favor or limit combinations with immune checkpoint inhibitors. We also map resistance along the delivery-to-kill cascade and integrate practical safety considerations, including interstitial lung disease/pneumonitis, hematologic toxicity, ocular events, and overlapping toxicities in combination regimens. Three principles emerge: ADC efficacy is a systems property; strategies that broaden tumor coverage may also increase normal-tissue exposure; and successful combinations require platform-specific rather than class-wide rationale. Future progress will depend on biomarker-guided sequencing, rational platform selection, and safety-adapted optimization of the therapeutic window.

Plain Language Summary

Antibody–drug conjugates are medicines that use an antibody to carry a strong anticancer drug toward tumor cells. They have improved treatment for several types of breast cancer, but their benefits and side effects vary between patients. This review explains why. Treatment success depends not only on the protein recognized by the antibody, but also on how the drug is linked to the antibody, how it is released, how far it spreads inside a tumor, and how the tumor and immune system respond. We also explain why some antibody–drug conjugates may work well with immunotherapy while others may not. Our main message is that better treatment requires balancing cancer killing with safety and selecting the right drug design for the right patient and treatment setting.

Introduction

Antibody-drug conjugates (ADCs) have evolved from proof-of-concept targeted therapies into a major class of anticancer agents.1–3 Canonical ADCs integrate three core components-an antigen-directed antibody, a chemical linker, and a highly potent cytotoxic payload-to increase tumor-selective drug delivery while limiting systemic exposure.1,2 Following target binding and internalization, ADCs are generally processed through endosomal-lysosomal pathways, leading to intracellular payload release.1,2 For ADCs carrying membrane-permeable payloads, released drug can also diffuse into neighboring antigen-low or antigen-negative cells and generate a bystander effect, an important mechanism for overcoming heterogeneous target expression.1–3 Consequently, the clinical performance of an ADC is determined not simply by cytotoxic potency or target expression, but by how effectively its molecular architecture balances tumor exposure against normal-tissue toxicity-that is, by the engineering of its therapeutic window.1–3

In breast cancer, this transition is particularly evident because ADCs are now active across multiple molecular subtypes and increasingly across different lines and stages of treatment.1–4 Sacituzumab govitecan (SG), a TROP2-directed ADC, first established a major role for this drug class in previously treated metastatic triple-negative breast cancer (TNBC),5,6 while subsequent Phase III studies have expanded TROP2-directed strategies into hormone receptor-positive/HER2-negative disease and other breast cancer settings.4,7 At the same time, the rapid expansion of ADC therapy has exposed important limitations, including heterogeneous target expression, resistance after sequential ADC exposure, and platform-specific toxicities that may restrict dose intensity or treatment duration.1–4,8

The HER2 field further illustrates how ADCs have blurred traditional biomarker boundaries. T-DXd demonstrated substantial clinical activity in HER2-low breast cancer, conventionally defined as HER2 immunohistochemistry (IHC) 1+ or IHC 2+ with negative in situ hybridization, thereby extending HER2-directed treatment beyond conventionally HER2-positive disease.9,10 More recently, the DESTINY-Breast06 trial demonstrated benefit from T-DXd in hormone receptor-positive metastatic breast cancer with HER2-low expression and also supported activity in the exploratory HER2-ultralow population, defined as IHC 0 with detectable membrane staining.11

Importantly, low HER2 expression should be distinguished from HER2 heterogeneity. HER2-low and HER2-ultralow describe levels of target expression, whereas HER2 heterogeneity refers to spatial or temporal variation in HER2 expression within a tumor, between tumor regions, or across different lesions.12,13 Such heterogeneity may limit uniform ADC binding and delivery, while membrane-permeable payloads and bystander killing can partially extend cytotoxic activity to neighboring cells with lower or absent target expression.12–15 These observations illustrate a central principle of ADC therapy: target abundance alone is insufficient to determine clinical activity; molecular design and the spatial organization of the tumor jointly shape the effective therapeutic window.1–3

Several recent reviews have comprehensively summarized ADC development, molecular design, breast cancer indications, resistance mechanisms, safety, and emerging platforms.4,16–19 However, these dimensions are frequently discussed as parallel topics rather than as interconnected determinants of the same clinical problem. The distinguishing perspective of the present review is therefore to use therapeutic-window engineering as a unifying framework linking ADC molecular architecture to tumor heterogeneity, clinical efficacy, resistance, immune modulation, and toxicity. From this perspective, increasing payload potency or broadening bystander activity is not inherently advantageous if the same modification increases systemic exposure or organ-specific toxicity; similarly, expanding target eligibility may improve tumor coverage while simultaneously increasing dependence on payload diffusion, intratumoral penetration, and patient-specific safety factors. Thus, rather than viewing individual ADC components in isolation, we focus on how their interactions determine the balance between effective tumor killing and treatment-limiting toxicity.

Within this framework, we first examine how target biology, antibody properties, linker stability and release chemistry, payload mechanism and physicochemical characteristics, drug-to-antibody ratio (DAR), conjugation homogeneity, and intratumoral delivery collectively determine ADC efficacy and safety.1–3 We then reassess the rapidly evolving clinical positioning and sequencing of ADCs across HER2-positive, HER2-low/ultralow, hormone receptor-positive/HER2-negative, and TNBC settings.4,20 Beyond direct cytotoxicity, we critically evaluate the immunomodulatory potential of ADCs, including immunogenic cell death, antigen release, Fc-mediated effector functions, and dendritic-cell activation,21–24 with particular emphasis on how payload class, linker properties, bystander activity, Fc biology, tumor heterogeneity, and baseline immune context may favor or constrain combinations with immune checkpoint inhibitors. Finally, resistance, toxicity, and next-generation conjugate strategies are integrated into the same therapeutic-window framework to identify priorities for biomarker-guided patient selection, ADC sequencing, rational combination therapy, and safety-adapted clinical implementation.1–4,20

As a narrative review, we conducted a focused search of PubMed/MEDLINE and Web of Science for English-language publications relevant to ADC development and breast cancer. Literature and regulatory information were updated through 31 August 2026, with priority given to pivotal clinical trials, recent high-quality reviews, mechanistic studies, and regulatory information directly relevant to ADC engineering, efficacy, resistance, immunotherapy combinations, and toxicity.

Foundational Principles of ADCs: Molecular Design as the Determinant of Efficacy and Therapeutic Window

ADCs have evolved from the concept of “targeted chemotherapy” into modular therapeutic platforms whose clinical performance can be optimized through molecular engineering.1–3 Within this framework, target and antibody properties, linker stability and release chemistry, payload mechanism and physicochemical characteristics, DAR, and conjugation homogeneity interact to determine tumor delivery, bystander activity, pharmacokinetic behavior, toxicity, and ultimately the therapeutic window.1–3 The major design determinants and their clinical consequences are summarized in Table 1, while their integrated effects on ADC performance and the therapeutic window are illustrated in Figure 1.

Table 1.

ADC Design Determinants and Clinical Consequences

Determinant	Key Variables	Efficacy Relevance	Therapeutic-Window Impact
Target/antibody	Antigen density, selectivity, affinity, internalization	Determines tumor uptake and coverage of heterogeneous lesions	On-target/off-tumor toxicity; excessive affinity may limit penetration
Linker	Cleavable vs non-cleavable, plasma stability, trigger specificity	Controls payload release and bystander potential	Premature release increases systemic toxicity; overly stable linkers may reduce tumor killing
Payload	Mechanism of action, membrane permeability, hydrophobicity, efflux sensitivity	Determines potency, bystander killing, and immunogenic cell death potential	Payload class shapes organ-specific toxicity and cross-resistance
DAR/conjugation	Average DAR, DAR distribution, conjugation site, homogeneity	Influences potency, exposure, PK, and tumor delivery	High-DAR or heterogeneous species may increase clearance and off-target toxicity
Tumor delivery context	Perfusion, ECM density, interstitial pressure, hypoxia	Limits penetration and core-region coverage	Dose escalation may increase toxicity more than efficacy

Figure 1.

Molecular design determinants of the ADC therapeutic window. Schematic overview illustrating how antibody–target binding and internalization, linker stability and release, payload mechanism of action and physicochemical properties, drug-to-antibody ratio (DAR), conjugation homogeneity, and hydrophobicity jointly determine ADC performance. These design variables influence effective tumor delivery, controlled payload release, cytotoxic killing and bystander diffusion, pharmacokinetic/pharmacodynamic behavior, and ultimately clinical efficacy and toxicity. The therapeutic window therefore reflects coordinated optimization of multiple molecular attributes rather than maximization of any single parameter. Green check marks indicate favorable effects on efficacy, whereas red warning triangles indicate increased toxicity risk or potential narrowing of the therapeutic window. Created in BioRender. Sun, L. (2026) https://BioRender.com/d8z9cxp.

The Three Core Components and Key Performance Attributes: System-Level Balancing of Antibody, Linker, Payload, and DAR

The efficacy and therapeutic window of an ADC are determined in the first instance by its molecular architecture, which needs coordinated optimization of three core elements - the antibody, linker and payload.1,2,25,26 Firstly, the antibody confers tumor selectivity through targeting of a chosen antigen, resulting in subsequent uptake by that cell type enabling precise delivery. Secondly, there is need for sufficient stability of the conjugate while circulating systemically but also adequate release within the tumor cell or tumor microenvironment, which requires correct design of the linker chemistry. Finally, the payload needs sufficient cytotoxicity to kill the malignant cells. All together therefore this combination decides about the full activity chain - whether the ADC can reach the tumor, if it will deliver the payload in the right place, and achieves effective cytotoxicity after release.2

Within this framework, DAR, conjugation site, and conjugation homogeneity are key design parameters that influence ADC stability, pharmacokinetics, and pharmacodynamic performance.27–30 And here again, having more is not generally better-there is evidence that increasing DAR leads to increased conjugate hydrophobicity, thus promoting aggregation and accelerating systemic clearance, which can lead ultimately to reduced overall therapeutic benefit.31 Manufacturing approaches therefore typically seek to minimize the presence of high-DAR, hydrophobic species in order to give improved predictability of exposure.

Payload physicochemical properties, in particular their degree of hydrophobicity-further complicate this balancing act: More hydrophobic payloads may enhance membrane permeability and strengthen bystander killing, which can be advantageous in heterogeneous tumors. However, increased hydrophobicity may also accelerate systemic clearance, promote aggregation or nonspecific uptake, and thereby narrow the therapeutic index.31 Possible optimization approaches consist here again mainly of careful tuning of the DAR-value but now with the aim of finding a good compromise between potency on the one hand and tolerability on the other; or alternatively of putting a hydrophilic mask over the drug part (PEGylation) so as to reduce its adverse effects without impeding its actual delivery.

These variables are interdependent rather than independently optimizable. Increasing DAR may enhance payload delivery per antibody molecule, but excessive drug loading can increase hydrophobicity, aggregation, and systemic clearance, thereby reducing effective tumor exposure and tolerability.27–31 Similarly, physicochemical modifications that improve payload permeability or bystander killing may increase coverage of heterogeneous tumors while simultaneously increasing normal-tissue exposure.31,32 Thus, ADC optimization should not aim to maximize any single molecular attribute. Instead, target engagement, tumor penetration, payload release, intracellular killing, pharmacokinetics, and systemic toxicity must be balanced collectively to maximize the therapeutic window.27,28,31,32

Linker Chemistry and Release Mechanisms, Bystander Effect, and Tumor Penetration

Linker design must resolve a classic trade-off: stability in circulation versus efficient on-site payload release.25,26 Broadly, linkers are classified as non-cleavable or cleavable. Non-cleavable linkers require complete lysosomal degradation of the antibody to generate an active, often residue-bearing payload species; they generally provide high systemic stability but may constrain the nature and extent of payload release. Cleavable linkers are designed to exploit tumor-associated or intracellular conditions, such as acidic pH, elevated reducing potential, or protease activity, thereby promoting payload release; when the released payload is membrane-permeable, this can also enhance bystander killing.33,34 However, increased lability can raise the risk of premature release and attendant systemic toxicity.

The bystander effect depends on membrane permeability and diffusibility of the released payload (or active metabolites), but is also shaped by linker-trigger specificity, the chemical form of the released species, and tumor-stromal diffusion constraints. Hydrophobic payloads tend to diffuse more readily from antigen-positive cells into neighboring antigen-low/negative cells, facilitating elimination of escape subclones. Yet this same property can increase exposure of normal tissues, narrowing the therapeutic window. Therefore, linker stability and payload physicochemical features must be co-optimized to achieve a tolerable balance between breadth of tumor coverage and systemic safety.35

Even when target expression is abundant, intratumoral penetration can become rate-limiting. High-affinity antibodies may be preferentially captured in perivascular regions, creating a “binding-site barrier” that limits diffusion into poorly perfused tumor areas.36 In tumors with low or heterogeneous antigen expression, membrane-permeable payloads and bystander killing can partially compensate for incomplete target coverage.12–15,37 However, broader payload diffusion is not uniformly advantageous because the same physicochemical properties that facilitate bystander killing may also increase exposure outside the intended tumor compartment.31,37 Accordingly, penetration and bystander activity should be considered complementary but potentially competing determinants of the therapeutic window.

Manufacturing and Conjugation: How Homogeneity Shapes the Therapeutic Window and the Trajectory of Technology

Conjugation chemistry and manufacturing directly influence ADC molecular heterogeneity, physicochemical behavior, pharmacokinetics, and therapeutic window. Conventional stochastic conjugation generates heterogeneous ADC populations with broad DAR distributions, whereas high-DAR and highly hydrophobic species may show increased aggregation and more rapid systemic clearance.27,31,38 Consequently, contemporary ADC development increasingly favors approaches that provide more controlled DAR distributions and improved product homogeneity.25,26

Several site-specific conjugation strategies have been developed, including engineered cysteine approaches, incorporation of noncanonical amino acids, and enzyme-mediated conjugation platforms.29,39 These technologies can improve molecular consistency and allow more precise control over conjugation site and drug loading.

Nevertheless, molecular homogeneity should not be viewed as an endpoint in itself. Site-specific conjugation can improve physicochemical consistency and pharmacokinetic predictability, but clinical efficacy still depends on coordinated optimization of target biology, antibody behavior, tumor penetration, linker-mediated release, and payload properties.1,2,40 Thus, manufacturing innovation expands the engineering space of ADCs but does not eliminate the fundamental requirement to balance efficacy and toxicity.

The Clinical Landscape of ADCs in Breast Cancer: Who Receives What, and When-Across Subtypes, Targets, and Lines of Therapy

The clinical positioning of ADCs in breast cancer has changed rapidly, with several agents moving from later-line metastatic treatment into first-line and, more recently, curative early-stage settings,16,41 because regulatory status varies across jurisdictions, the discussion below primarily reflects major randomized clinical evidence and current United States regulatory positioning, with regulatory information updated through 31 August 2026. Rather than presenting ADCs as a static list of approved agents, we organize the clinical landscape by target, molecular subtype, and treatment setting to illustrate how molecular design and tumor biology increasingly influence treatment selection and sequencing.1,16–18,41

Validated Targets and Representative Agents: An Integrated View Across Targets, Subtypes, and Treatment Lines

HER2- and TROP2-directed ADCs currently represent the most clinically established ADC classes in breast cancer.4,16,19 Along the HER2 axis, T-DM1 established the clinical feasibility of HER2-directed ADC therapy, whereas T-DXd subsequently demonstrated superior efficacy in previously treated HER2-positive metastatic disease.42–44 The clinical position of T-DXd has now moved substantially earlier. In the phase III DESTINY-Breast09 trial, first-line T-DXd plus pertuzumab significantly prolonged progression-free survival compared with taxane, trastuzumab, and pertuzumab in HER2-positive advanced or metastatic breast cancer.45

ADCs have also entered curative HER2-positive treatment settings. In DESTINY-Breast11, neoadjuvant T-DXd followed by paclitaxel, trastuzumab, and pertuzumab improved pathological complete response compared with the conventional anthracycline-containing regimen in high-risk early HER2-positive breast cancer.46 In the post-neoadjuvant setting, DESTINY-Breast05 demonstrated superior invasive disease-free survival with T-DXd compared with T-DM1 in patients with residual invasive HER2-positive disease.47 These developments have resulted in the clinical movement of HER2-directed ADCs from advanced disease into both neoadjuvant and adjuvant therapy.

T-DXd has simultaneously expanded HER2-directed treatment beyond conventionally HER2-positive disease. DESTINY-Breast04 established its activity in previously treated HER2-low advanced breast cancer,9,10 whereas DESTINY-Breast06 demonstrated benefit in hormone receptor-positive HER2-low and HER2-ultralow metastatic breast cancer after endocrine therapy.11 This evolution underscores that HER2-directed ADC activity depends not only on conventional HER2 amplification or overexpression but also on target distribution, payload properties, and bystander activity.

The TROP2 landscape has evolved in parallel. SG initially established TROP2-directed ADC therapy in previously treated metastatic TNBC and subsequently demonstrated survival benefit in hormone receptor-positive/HER2-negative metastatic breast cancer.6,48 Dato-DXd has also become clinically established in previously treated hormone receptor-positive/HER2-negative metastatic disease on the basis of TROPION-Breast01.7 More recently, both agents have moved into first-line TNBC. ASCENT-03 demonstrated superior progression-free survival with SG compared with chemotherapy in patients with previously untreated advanced TNBC who were not candidates for PD-1/PD-L1 inhibitor therapy.49 TROPION-Breast02 similarly established first-line Dato-DXd in an immunotherapy-ineligible population.50 In PD-L1-positive advanced TNBC, SG plus pembrolizumab has also demonstrated phase III superiority over chemotherapy plus pembrolizumab.51

Beyond HER2 and TROP2, additional targets and ADC formats continue to be explored, particularly in TNBC, but most remain investigational.52,53 Accordingly, the current clinical landscape should distinguish agents with randomized evidence and established clinical roles from emerging programs that remain under evaluation.

A Subtype-Based Perspective: Therapeutic Logic and ADC Sequencing Across Breast Cancer Categories

HER2-Positive

HER2-Positive Breast Cancer

ADCs have moved progressively earlier in the HER2-positive treatment continuum. In metastatic disease, T-DXd plus pertuzumab has emerged as a first-line strategy on the basis of DESTINY-Breast09, whereas T-DXd remains central to subsequent HER2-directed treatment.45 T-DM1 remains clinically relevant but now occupies a narrower position within an increasingly crowded HER2-directed sequence.42–44 Importantly, T-DXd has also entered curative treatment: DESTINY-Breast11 supports a neoadjuvant T-DXd-based strategy, whereas DESTINY-Breast05 establishes T-DXd as a post-neoadjuvant option for residual invasive disease.46,47 These changes make sequencing, cumulative toxicity, and cross-resistance increasingly important rather than purely theoretical considerations.20,41,54–57

HER2-Low/Ultralow

HER2-Low and HER2-Ultralow Breast Cancer

HER2-low disease established the principle that clinically meaningful HER2-directed ADC activity does not require conventional HER2 amplification or overexpression.9,10 DESTINY-Breast06 further extended this concept to hormone receptor-positive HER2-low and HER2-ultralow metastatic disease after endocrine therapy.11 However, these findings should not be interpreted as evidence that antigen abundance is irrelevant. Rather, T-DXd activity in low-expression tumors reflects the interaction among target-mediated delivery, cleavable linker chemistry, a membrane-permeable payload, and bystander killing.12–15,58 Spatial and temporal HER2 heterogeneity therefore remains clinically relevant.

TNBC

Triple-Negative Breast Cancer

TROP2-directed ADCs have moved from salvage therapy into first-line treatment. SG remains established in previously treated disease,5,6,59 but ASCENT-03 now supports first-line SG in patients who are not candidates for checkpoint inhibition.49 Dato-DXd provides another first-line ADC option for patients who are not candidates for PD-1/PD-L1 inhibitors.50 In PD-L1-positive disease, ASCENT-04/KEYNOTE-D19 demonstrated that SG can replace conventional chemotherapy as the cytotoxic partner of pembrolizumab.51 Thus, the central clinical question is shifting from whether ADCs are active in TNBC to how TROP2-directed ADCs and ADC–ICI regimens should be selected and sequenced according to immune eligibility, prior exposure, payload class, and resistance mechanism.

HR+/HER2−

Hormone Receptor-Positive/HER2-Negative Breast Cancer

ADC selection in this setting increasingly depends on both HER2 expression and prior systemic treatment. T-DXd provides an earlier ADC option after endocrine therapy for HER2-low or HER2-ultralow disease.11 Dato-DXd is established after prior endocrine-based therapy and chemotherapy,7 whereas SG remains an evidence-based option in later-line metastatic disease.48 Because several available ADCs deliver topoisomerase-I inhibitor payloads, the optimal sequence is unresolved, and emerging evidence of payload-related cross-resistance supports mechanism-informed rather than target-only sequencing.54–57

Reframing Mechanisms of Action: From Targeted Cytotoxic Delivery to Tumor Microenvironment Remodeling

ADCs were initially conceptualized primarily as vehicles for tumor-selective cytotoxic delivery.60 However, accumulating preclinical and translational evidence indicates that selected ADC platforms can also influence tumor immunogenicity and the surrounding immune microenvironment.21–24,60 Importantly, these immunomodulatory effects are not uniform across ADCs and depend on payload mechanism, antibody and Fc properties, linker behavior, tumor-cell death programs, and baseline immune context.21–24,60,61

Immunostimulatory Effects: ADCs as “Igniters” for Antitumor Immunity

ADC-mediated immune activation is supported most strongly by preclinical and translational evidence rather than by a universal clinical class effect.21–24,60 Several ADC payloads can induce cellular stress and features associated with immunogenic cell death (ICD), including calreticulin exposure, ATP release, and HMGB1 release.22,23,62–65 These signals can promote dendritic-cell maturation and antigen cross-presentation, thereby facilitating tumor-specific T-cell priming.62–65 However, the magnitude of ICD varies according to payload class, payload concentration, tumor-cell sensitivity, and ADC delivery efficiency, and therefore should not be assumed to occur equivalently with every ADC platform.22–24,60

ADC-induced tumor-cell death can also increase the availability of tumor-associated antigens and potentially facilitate epitope spreading.66 In spatially heterogeneous tumors, expansion of the antigenic repertoire recognized by T cells could theoretically contribute to immune control of target-low or target-negative subclones.36,58,66,67 Nevertheless, the extent to which ADC-induced epitope spreading materially contributes to clinical benefit remains less well established than direct payload-mediated cytotoxicity.

Many ADCs retain IgG Fc domains capable of engaging Fcγ receptors and supporting context-dependent immune effector functions, including antibody-dependent cellular cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis (ADCP).68,69 Through these mechanisms, natural killer cells and macrophages may contribute to the elimination of antibody-bound tumor cells. However, Fc-mediated activity varies according to antibody isotype, Fc engineering, target density, and the local immune environment and should therefore not be considered a uniform property of all ADCs.68,69

Collectively, direct tumor-cell killing, antigen release, dendritic-cell activation, and context-dependent Fc-mediated effects provide a mechanistic rationale for combining selected ADC platforms with immune checkpoint blockade.21–24,64,68,69 However, whether these mechanisms translate into clinically meaningful synergy depends on the molecular properties of the individual ADC and the immune context of the treated tumor.

Spatial Delivery Constraints and Microenvironmental Heterogeneity: Physical and Biological Barriers to Durable Efficacy

Despite their potential immunomodulatory effects, ADCs remain subject to the physical delivery constraints that limit macromolecular therapeutics in solid tumors.36,70 Abnormal vasculature, elevated interstitial fluid pressure, and dense extracellular matrix can reduce convective transport and diffusion, thereby generating heterogeneous intratumoral ADC exposure.70–75 These barriers become particularly consequential when antigen expression itself is low or spatially heterogeneous.12,36,58

Intratumoral spatial heterogeneity further complicates treatment responses. Hypoxic and acidified tumor cores can be associated with immune desert or immune-excluded phenotypes characterized by sparse T-cell infiltration and functional suppression.76 In these regions, ADC delivery itself is also frequently suboptimal.36,70–72 Consequently, heterogeneous antibody distribution may lead to incomplete tumor coverage and contribute to the emergence of resistant cell populations.36 Such spatially partitioned activity is not readily overcome by dose escalation alone, because any gain in tumor penetration may be offset by dose-limiting off-target toxicity.36,77

Accordingly, the ultimate efficacy of ADCs in breast cancer is not determined solely by cytotoxic potency. In some ADC settings, therapeutic activity may also depend on the nature of tumor cell death induced and the extent to which local immune activation is triggered.21,24 Recognizing—and addressing—the constraints imposed by delivery barriers and immunosuppressive microenvironments remains critical for improving ADC efficacy in solid tumors.36,70 Future optimization will require strategies to overcome delivery barriers and improve intratumoral distribution.36,70

Combination Therapy Focus: Synergy and Challenges of ADCs with Immune Checkpoint Inhibitors

Combining ADCs with immune checkpoint inhibitors (ICIs) is biologically attractive because selected ADCs can increase tumor-cell death, antigen release, and immune activation, whereas ICIs can reinvigorate antitumor T-cell responses.1,8,21–24,78–80 However, ADC–ICI synergy should not be regarded as a class effect. Molecular features that increase immune engagement may simultaneously increase systemic toxicity, and the benefit–risk relationship differs substantially among ADC platforms.8,18,78,81,82 Accordingly, the key translational question is not simply whether ADCs can be combined with ICIs, but which ADC architecture, tumor context, and patient population are most likely to generate clinically meaningful synergy.

Platform Features That Favor or Limit ADC–ICI Synergy

The capacity of an ADC to cooperate with checkpoint blockade begins with its payload. Payloads differ in their ability to induce cellular stress, inflammatory signaling, and immunogenic features of tumor-cell death.22–24,60,62–65 Consequently, two ADCs directed against similar targets may have substantially different immunological consequences if they deliver different payload classes or achieve different intracellular payload concentrations. At present, much of the mechanistic evidence linking payload-mediated ICD to enhanced checkpoint blockade remains preclinical, and clinical synergy should therefore not be inferred from ICD potential alone.21–24,60

Linker chemistry and payload permeability provide a second layer of variation. Cleavable linkers and membrane-permeable payloads can increase bystander killing, extend cytotoxicity into antigen-low tumor regions, and increase tumor-antigen release.12,14,24,33–35,37 These properties may be particularly advantageous in heterogeneous tumors. Conversely, broader payload diffusion and premature systemic release may increase hematologic, gastrointestinal, or organ-specific toxicity and narrow the therapeutic window.18,31,77 Thus, molecular features that improve intratumoral coverage may simultaneously reduce the tolerability of an ADC–ICI combination.

Fc biology represents another source of platform-specific variation. ADCs with preserved Fcγ receptor engagement may recruit natural killer cells and macrophages through ADCC or ADCP, whereas platforms with attenuated Fc function may depend predominantly on payload-mediated immune effects.68,69 Target density, intratumoral penetration, and spatial antigen heterogeneity further determine where sufficient ADC accumulates to initiate these processes.12,36,58 Tumors characterized by poor ADC penetration, immune exclusion, or profound T-cell dysfunction may therefore remain poorly responsive even when the ADC payload has potentially immunogenic properties.70–76,83–85

Taken together, payload mechanism, linker stability, bystander activity, Fc biology, target distribution, and baseline immune context jointly determine the probability of ADC–ICI synergy. These considerations favor platform-specific development of ADC–ICI combinations rather than extrapolation of clinical success from one ADC to the entire class. The platform-specific mechanisms underlying ADC–ICI synergy and the principal concerns regarding overlapping toxicities are summarized in Figure 2.

Figure 2.

Mechanistic rationale and safety considerations for combining ADCs with immune checkpoint inhibitors. ADCs may promote antitumor immunity through immunogenic cell death (ICD), characterized by endoplasmic reticulum stress, calreticulin exposure, ATP and HMGB1 release, followed by dendritic-cell uptake, antigen cross-presentation, CD8⁺ T-cell priming, and epitope spreading. Selected ADC platforms may additionally engage Fcγ receptor-dependent innate immune mechanisms, including natural killer cell-mediated antibody-dependent cellular cytotoxicity (ADCC) and macrophage-mediated antibody-dependent cellular phagocytosis (ADCP). Adaptive PD-L1 upregulation may restrain activated T-cell responses, providing a mechanistic basis for PD-1/PD-L1 checkpoint blockade. Potential overlapping toxicities of ADC–ICI combinations include myelosuppression, interstitial lung disease (ILD)/pneumonitis, and gastrointestinal toxicity or immune-mediated colitis. Red blocking marks indicate interruption of PD-1/PD-L1 signaling by immune checkpoint blockade, whereas yellow warning triangles indicate potential overlapping toxicity risks. Created in BioRender. Sun, L. (2026) https://BioRender.com/9ihhi8e.

Clinical Evidence: Distinguishing Established Benefit from Investigational Combinations

Clinical evidence for ADC–ICI combinations is heterogeneous and should be interpreted according to ADC platform, breast cancer subtype, treatment setting, and level of evidence. In HER2-positive disease, T-DM1 plus atezolizumab and T-DXd plus nivolumab have demonstrated the feasibility of combining HER2-directed ADCs with checkpoint blockade.78,86 However, these studies have not established a broadly applicable ADC–ICI standard in HER2-positive breast cancer. Thus, in this setting, the mechanistic rationale currently remains stronger than the evidence supporting routine clinical implementation.

TNBC provides the clearest clinical validation of the ADC–ICI concept. In ASCENT-04/KEYNOTE-D19, SG plus pembrolizumab significantly prolonged progression-free survival compared with chemotherapy plus pembrolizumab in previously untreated PD-L1-positive advanced TNBC.51 This finding is clinically important because it demonstrates that an ADC can replace conventional chemotherapy as the cytotoxic backbone of first-line checkpoint-based therapy in a biomarker-defined TNBC population. The regimen subsequently entered first-line clinical practice in the United States for PD-L1 CPS ≥10 disease.

Nevertheless, this success should not be generalized to all ADC–ICI combinations. Other programs, including Dato-DXd plus durvalumab and additional HER2- or TROP2-directed combinations, remain under investigation.87,88 Differences in payload mechanism, linker characteristics, Fc activity, tumor immune context, and toxicity profile may result in substantially different benefit–risk relationships. Ongoing trials should therefore determine not only whether an ADC–ICI regimen improves outcomes but also which biological features identify patients who derive incremental benefit from checkpoint blockade.

Overall Evidence and Limitations: Current Status and Key Directions

Taken together, the evidence for ADC–ICI combinations has moved beyond uniformly early-stage investigation. SG plus pembrolizumab now has randomized phase III evidence supporting first-line treatment of PD-L1-positive advanced TNBC,51 whereas most other ADC–ICI combinations remain investigational. This distinction is important because clinical success with one platform does not establish ADC–ICI synergy as a class effect.

Future development should therefore prioritize three questions: which patients are immunologically and molecularly suited to ADC–ICI therapy; which ADC features generate a favorable efficacy–toxicity balance when combined with checkpoint blockade; and whether concurrent administration is superior to sequential treatment.8,24,60,89,90 Until these questions are addressed prospectively, ADC–ICI development should remain mechanism- and biomarker-driven rather than based on the assumption that adding checkpoint blockade will uniformly improve ADC efficacy.

Resistance and Heterogeneity: Critical Failure Points Along the ADC Efficacy Chain

Despite the clinical success of ADCs, both primary and acquired resistance remain common in breast cancer.91 ADC activity requires successful completion of a multistep delivery-to-kill cascade encompassing target recognition, internalization, intracellular trafficking, payload release, and execution of tumor-cell death.92–94 Failure at any one of these steps can create a functional resistance breakpoint, while intratumoral and interlesional heterogeneity can produce different breakpoints within the same patient.91,95,96 The major resistance nodes along the ADC delivery-to-kill cascade are summarized in Figure 3, while their associated clinical phenotypes and potential optimization strategies are outlined in Table 2.

Figure 3.

Delivery-to-kill cascade and major resistance breakpoints of ADC therapy. The ADC efficacy cascade comprises six major steps: (1) target-antigen availability and heterogeneous expression; (2) extravasation and intratumoral penetration; (3) receptor binding and internalization; (4) endosomal–lysosomal trafficking and processing; (5) payload release from cleavable or non-cleavable linker systems; and (6) cytotoxic killing and bystander activity. Resistance may arise at multiple levels, including antigen loss or heterogeneity, poor tumor penetration and binding-site barriers, impaired internalization or lysosomal processing, drug efflux or detoxification, and altered cell-death thresholds. Hypoxic or acidic tumor regions, dense extracellular matrix, abnormal vasculature, elevated interstitial pressure, and immune exclusion may further restrict intratumoral ADC delivery. Red warning triangles indicate major resistance or delivery-failure nodes along the ADC delivery-to-kill cascade. Created in BioRender. Sun, L. (2026) https://BioRender.com/9e7qxh5.

Table 2.

ADC Response Failure Points and Potential Optimization Strategies

Step	Failure Node	Clinical Phenotype	Potential Strategy
Target presence	Antigen loss, low expression, spatial/interlesional heterogeneity	Mixed response; early escape	Switch target; dual-target/bispecific ADCs; bystander-capable platforms
Binding/internalization	Weak binding, poor internalization, altered trafficking	Target-positive but insensitive disease	Optimize epitope, affinity, and antibody internalization properties
Lysosomal processing/release	Lysosomal dysfunction, inadequate cleavage	Primary or acquired resistance	Linker redesign; tumor-conditional release strategies
Payload handling	Efflux pumps, detoxification pathways	Cross-resistance to similar payloads	Change payload class; efflux-resistant or dual-payload ADCs
Cell-death execution	DNA repair activation, apoptotic threshold increase	Short-lived response; relapse	Combine with DDR/apoptosis modulators or immune-amplifying strategies
Microenvironment barriers	Poor perfusion, dense stroma, hypoxia, immune exclusion	Core-region persistence; local progression	Improve penetration/perfusion; leverage bystander effect; rational sequencing
Combination safety	Overlapping lung, GI, marrow, or immune-related toxicities	Higher-grade AEs; diagnostic ambiguity	Baseline risk stratification, close monitoring, early workup, dose/schedule optimization

A Mechanistic Framework for Resistance: Stepwise Deconstruction of the Delivery-to-Kill Cascade

Resistance to ADCs can be systematically mapped to specific biological steps along the ADC pathway.92–94 The first major breakpoint occurs at the target level, including treatment-driven downregulation or loss of antigen expression, spatial heterogeneity within lesions and discordance across metastatic sites, and phenotypic reprogramming, including EMT-associated target downregulation or subtype switching, that reduces target abundance.97–99 In HER2-low breast cancer, where HER2 expression is limited and frequently heterogeneous, variation in target abundance may influence the activity of HER2-directed ADCs.58,100

A second breakpoint involves impaired target engagement, defective internalization, and aberrant endocytic trafficking.92–94,101 Even when the target is present, low internalization efficiency—or preferential trafficking toward recycling rather than degradative pathways—can markedly diminish payload release.92–94,101 In addition, lysosomal dysfunction (impaired acidification or reduced protease activity) may compromise linker cleavage and/or antibody catabolism, preventing effective liberation of the active payload.92–94,101,102

A third layer of resistance arises from intracellular handling of the released payload.92–94 Once released, payload molecules may be exported by drug efflux pumps, particularly ATP-binding cassette (ABC) transporters, or detoxified by intracellular glutathione-dependent systems such as glutathione S-transferases (GSTs).103,104 These mechanisms reduce the intracellular concentration of active payload and are commonly implicated in gradually emerging acquired resistance; emerging evidence suggests that cross-resistance is more likely when sequential ADCs share the same payload mechanism, whereas switching to a mechanistically distinct payload class may preserve activity.54–57

Finally, resistance can develop at the level of payload targets and cell-death execution.92–94 Tumor cells may attenuate payload cytotoxicity through alterations in the payload’s molecular target and associated downstream signaling pathways.92–94 More fundamentally, resistance can arise through alterations in downstream cellular response pathways that reduce the cytotoxic effects of ADC payloads.92–94

Breast Cancer Heterogeneity: The Biological Basis of Mixed Responses and Focal Escape

Heterogeneity provides an important context for ADC response variability in breast cancer.91,95,96,105 There are many types of heterogeneity in breast cancer: first, different molecular subtypes have very dissimilar baseline biology (HER2-positive, TNBC, HR-positive disease).91,105 Second, within a given patient, different metastatic lesions, and even distinct regions within a single lesion, can vary substantially in antigen expression, genomic or molecular features, and immune microenvironmental states.106–108 Third, in terms of their spatial architecture some tumors contain hypoxic regions, stromal barriers and immunosuppressive microenvironments, all of which can physically block drugs reaching cells and make it hard for immune cells to enter tumors.109–111

These forms of heterogeneity can influence ADC efficacy at multiple levels simultaneously.91,92 Uneven antigen distribution and intratumoral drug penetration generate spatially variable payload exposure, whereas impaired internalization, altered intracellular trafficking, efflux, and detoxification can create additional cell-intrinsic resistance.112,113 Clinically, these mechanisms may manifest as mixed radiographic responses or focal progression. Although preclinical studies indicate that selected ADCs can induce immunogenic cell death, the extent to which heterogeneous ADC distribution also creates spatially heterogeneous immune activation—and thereby limits the efficacy of ADC–ICI combinations—remains insufficiently understood.15,21,24

Strategies to Overcome Resistance: From Mechanistic Insight to Engineering and Clinical Translation

In response to resistance and heterogeneity, next-generation ADC engineering and clinical strategies are increasingly oriented toward building system-level robustness.91,105,114–116 On the engineering front, bispecific or dual-target ADCs aim to reduce failure driven by loss or uneven expression of a single antigen by simultaneously engaging complementary targets.105,114 Dual-payload or mixed-payload ADCs seek to overcome resistance to a single mechanism of action by delivering cytotoxic modalities with distinct targets or cellular effects (combining microtubule disruption with DNA-damaging activity), thereby broadening cell-killing coverage across heterogeneous tumor populations.115–117 Conditionally activated ADCs are designed to increase tumor selectivity, enhance local activity, and minimize off-tumor toxicity, thereby improving the therapeutic index and expanding the therapeutic window.118

Mechanistic characterization of resistance may eventually help guide ADC sequencing.91,105,119 If progression is driven predominantly by loss or marked reduction of the target antigen, switching to another ADC directed against the same target may provide limited benefit unless sufficient target expression is retained.103,119 In contrast, when resistance occurs primarily at the payload level, an ADC carrying a mechanistically distinct payload may retain activity even if the same antigen is targeted.54–57 These observations are particularly relevant as multiple breast cancer ADCs now use topoisomerase-I inhibitor payloads and are increasingly administered sequentially.

Dynamic monitoring through repeat tissue profiling or liquid biopsy may help distinguish target loss from payload-related or downstream resistance and may therefore inform subsequent ADC selection.120–122 However, prospective evidence demonstrating that resistance-guided sequencing improves clinical outcomes is still limited. Accordingly, mechanism-based sequencing should currently be viewed as a rational framework for clinical investigation rather than an established treatment algorithm.

Safety and Toxicity Management: Defining and Expanding the Therapeutic Window

The central value proposition of ADC therapy lies in its therapeutic window—the balance between antitumor efficacy and treatment-related toxicity.18,123 Although ADCs are designed to enhance tumor-selective drug delivery, clinically relevant systemic and organ-specific toxicities remain common.18,123–125 As these agents move into earlier treatment settings and combination regimens, proactive toxicity prevention, monitoring, and management become increasingly important for preserving treatment exposure and clinical benefit.89,126,127

Typical Toxicity Profiles and Organ-Specific Management

ADC toxicities arise from contributions of all three components: payload-mediated cytotoxicity, biology linked to the antibody/target, and systemic payload release related to linker instability.18,123 In clinical practice, ADC toxicity monitoring and management are commonly organized according to the major toxicity domains involved, such as pulmonary, ocular, hematologic, gastrointestinal, and neurologic adverse events.126,128

Myelosuppression is a common and sometimes dose-limiting ADC-associated toxicity, typically manifesting as neutropenia, anemia, and thrombocytopenia, and is largely related to payload-driven off-target effects, with the dominant pattern varying by payload class.129,130 Management generally includes baseline assessment of marrow reserve and relevant clinical risk factors, regular hematologic monitoring during treatment, and timely supportive measures or dose modification when clinically significant cytopenias occur.130–132 Interventions include dose delays, dose reductions, and granulocyte colony-stimulating factor support when appropriate. A central clinical balance is maintaining sufficient dose intensity while preventing severe infections and treatment interruptions driven by hematologic toxicity.

Peripheral neuropathy has been reported at a higher incidence in ADCs carrying microtubule-disrupting payloads such as MMAE, and is clinically characterized by sensory symptoms including paresthesia and numbness.133 Management of ADC-associated peripheral neuropathy involves risk assessment, early recognition, and dose modification strategies; however, detailed approaches extend beyond the scope of this review summary.133

Hepatotoxicity commonly manifests as elevations in serum transaminases, particularly ALT and AST.130,134 Management generally relies on baseline and on-treatment monitoring of liver function, with treatment modification considered according to the severity of abnormalities.134,135 Decisions typically follow structured algorithms involving treatment interruption, reassessment, and severity-guided dose modification.

Ocular toxicity is a recognized adverse effect of certain ADCs and may include corneal epitheliopathy or microcyst-like epithelial changes, dry eye, and blurred vision.136,137 Effective management often benefits from multidisciplinary coordination and ophthalmologic involvement, particularly for ADCs with recognized ocular risk.124,138 When there are clinically meaningful ocular events dose interruption or dose modification are usually required.

A High-Consequence Risk: Management of Interstitial Lung Disease/Pneumonitis

ILD/pneumonitis is a clinically important and potentially fatal toxicity associated particularly with T-DXd.81,82,139,140 Management depends on early recognition. Baseline assessment of pulmonary risk and prompt evaluation of new respiratory symptoms, including cough and dyspnea, are essential, with treatment interruption when ILD/pneumonitis is suspected.81,82,139,140 Systemic corticosteroids should be initiated promptly when clinically indicated. For T-DXd, treatment may be reconsidered after complete resolution of grade 1 ILD/pneumonitis, whereas permanent discontinuation is generally recommended for grade ≥2 events.82,141 As ADCs move into earlier disease settings, longer treatment durations, and combination regimens, proactive ILD surveillance becomes increasingly important to preserve the therapeutic window.131,142,143

Overlapping Toxicities in Combination Therapy and Integrated Management

Toxicity management in patients receiving ICIs can be complex and requires careful monitoring and multidisciplinary management.144–146 In ADC-ICI combination regimens, overlapping clinical syndromes may complicate attribution of toxicity. For example, diarrhea may reflect ADC-related gastrointestinal toxicity, whereas ICIs can cause immune-mediated colitis; similarly, pulmonary symptoms may reflect ADC-related ILD or ICI-related pneumonitis.130,147,148 These considerations support a stratified, pathway-based approach to toxicity management.144–146

First, baseline clinical assessment and review of relevant comorbidities and organ function are important to guide the intensity of monitoring and facilitate early recognition of treatment-related toxicity.149–151 Second, focused surveillance of overlapping “at-risk” organs—particularly the lung, liver, gastrointestinal tract, skin, and bone marrow—should be paired with clear differential-diagnosis workflows.144–146 For example, new or worsening respiratory symptoms should prompt immediate evaluation for possible ILD/pneumonitis.82,139,152

In ADC–ICI combinations, toxicity management requires both rapid intervention and accurate attribution. Severe immune-related adverse events generally require interruption of immunotherapy and guideline-directed immunosuppression,144–146 whereas payload-driven toxicities such as myelosuppression are managed primarily through ADC interruption, dose reduction, supportive treatment, or schedule modification.130–132 Because pulmonary, gastrointestinal, hepatic, and hematologic syndromes may overlap between the two drug classes, multidisciplinary assessment and structured differential-diagnosis pathways are particularly important.8,89,144–146

Next-Generation ADC Strategies and Precision Implementation

Next-generation ADC development in breast cancer is shifting from maximizing cytotoxic potency toward optimizing the entire therapeutic system: selectivity, tumor delivery, payload release, resistance avoidance, and toxicity control.1,90,91,153–159 This shift is particularly relevant in HER2-low and TNBC, where spatial antigen heterogeneity, stromal barriers, prior ADC exposure, and immune context can all influence efficacy.91,153–157 Accordingly, innovation should be judged by whether it expands the effective therapeutic window, rather than by molecular novelty alone.

Several emerging formats are being developed to address these limitations. Bispecific or dual-target ADCs may improve tumor coverage by engaging more than one antigen and may help reduce escape driven by single-target heterogeneity.1,90,158–160 Conditionally activated or masked ADCs are designed to improve selectivity by restricting payload delivery or antibody activation to tumor-associated microenvironmental cues, such as protease activity or acidic pH.1,90,158,159 Dual-payload ADCs may broaden cytotoxic mechanisms and potentially reduce payload-specific resistance, although their clinical value will depend on whether increased mechanistic complexity can be achieved without excessive toxicity.1,90,158,159

Importantly, greater molecular complexity does not necessarily translate into a wider therapeutic window. Bispecific targeting may improve tumor coverage but can introduce additional normal-tissue binding; dual-payload strategies may reduce single-payload resistance while increasing manufacturing complexity and cumulative toxicity; and conditional activation depends on sufficiently selective tumor-associated triggers.114–118 Thus, these next-generation formats remain promising but should be evaluated according to whether their added biological complexity produces a measurable improvement in tumor selectivity, exposure, and tolerability.

Immune-stimulating antibody conjugates further expand the ADC concept by linking targeted delivery with local immune activation, providing a potential bridge between ADC therapy and immunotherapy-based combinations.161–163

Beyond molecular format, several design levers remain central. Target selection should incorporate not only antigen abundance, but also tumor selectivity, spatial distribution, internalization efficiency, and normal-tissue expression. Payload choice should consider potency, membrane permeability, efflux susceptibility, immunogenic cell-death potential, and organ-specific toxicity. Linker design must balance systemic stability with efficient intratumoral or intracellular release. Conjugation chemistry and DAR control are also critical because highly heterogeneous or hydrophobic ADC species may compromise pharmacokinetics, tumor exposure, and tolerability.1,29,40,90,158,159

Precision implementation will be as important as molecular innovation. Patient selection should move beyond single antigen-expression thresholds toward integrated assessment of spatial target heterogeneity, tumor delivery, immune context, payload-relevant resistance mechanisms, and baseline organ-specific toxicity risk.120,121,164,165 These features may help determine not only whether a patient is likely to respond to an ADC, but also which ADC should be selected, when it should be introduced, and whether combination therapy is justified.

Ultimately, the most successful next-generation ADC may not be the platform with the highest DAR, most potent payload, or broadest bystander effect, but the one that most effectively matches molecular design to the biological constraints of the individual tumor while maintaining tolerable systemic exposure. This principle connects next-generation engineering directly to biomarker-guided sequencing, rational combination strategies, and safety management, as summarized in Figure 4.

Figure 4.

Next-generation ADC strategies and biomarker-guided clinical implementation. (A) Representative next-generation conjugate formats, including bispecific/dual-target ADCs, conditionally activated or masked ADCs, dual-payload ADCs, immune-stimulating antibody conjugates, and protein-degrader antibody conjugates. (B) Core molecular design levers, including target selection, payload choice, antibody/carrier engineering, linker innovation, and DAR/conjugation control. (C) Precision clinical implementation integrating spatial target heterogeneity, imaging and stromal features, immune contexture, and organ-function/toxicity risk to guide ADC sequencing, concurrent or sequential combination strategies, rational partner selection, and safety monitoring. Created in BioRender. Sun, L. (2026) https://BioRender.com/j1xcp8t.

Conclusion

Three conclusions emerge from the current ADC landscape in breast cancer. First, ADC efficacy is a systems property rather than a consequence of target expression alone. Antigen distribution, antibody properties, linker behavior, payload mechanism, DAR, intratumoral penetration, and intracellular processing jointly determine whether sufficient active payload reaches malignant cells without unacceptable normal-tissue exposure.

Second, tumor heterogeneity creates a fundamental therapeutic trade-off. Bystander-capable and membrane-permeable platforms may improve coverage of antigen-low or antigen-negative subclones, but the same properties can increase off-tumor exposure and narrow the safety margin. Thus, molecular characteristics that improve efficacy cannot be evaluated independently from their effects on toxicity.

Third, ADC–immunotherapy combinations should be developed on a platform-specific rather than class-wide basis. Payload immunogenicity, linker behavior, Fc activity, target distribution, baseline immune context, and overlapping toxicity all influence whether checkpoint blockade adds meaningful benefit.

The next phase of ADC development will therefore depend less on simply identifying additional targets and more on matching the appropriate molecular platform to tumor biology and clinical context. Biomarker-guided selection, mechanism-informed sequencing, rational combination design, and proactive toxicity management should be considered integral components of therapeutic-window engineering. This framework provides a unifying basis for translating future ADC innovation into durable clinical benefit.

Funding Statement

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Data Sharing Statement

Data sharing is not applicable to this article because no datasets were generated or analyzed during the current review.

Ethics Approval and Consent to Participate

The ethics statement is not applicable.

Author Contributions

All authors made a significant contribution to the work reported, whether that is in the conception, study design, execution, acquisition of data, analysis and interpretation, or in all these areas; took part in drafting, revising or critically reviewing the article; gave final approval of the version to be published; have agreed on the journal to which the article has been submitted; and agree to be accountable for all aspects of the work.

Disclosure

The authors declare no conflict of interest.