HER2, a member of the pan-HER receptor tyrosine kinase family, serves as a pivotal oncogenic driver in NSCLC. HER2 activation in NSCLC encompass three primary mechanisms: activating mutations (incidence: 1-6.7%), gene amplifications (1.4-22%), and protein overexpression (6-35%), with mutation frequencies notably elevated in Chinese populations (93, 94). HER2 activation promotes oncogenic signaling networks that promote tumor proliferation, survival, invasion, and epithelial-mesenchymal transition, correlating with aggressive disease progression, enhanced metastatic potential, resistance to EGFR tyrosine kinase inhibitors (EGFR-TKIs), and unfavorable clinical outcomes (10, 28, 70, 95).

Multiple ADCs targeting HER2 have demonstrated clinically meaningful antitumor activity in HER2-positive NSCLC. Trastuzumab emtansine (T-DM1), which conjugates anti-HER2 monoclonal antibody trastuzumab to the microtubule inhibitor DM1, induces HER2 internalization and lysosomal degradation, resulting in targeted intracellular payload release (96–98). The phase II study(Clinical trial number:JapicCTI-194620) (99) enrolled 22 patients with HER2 exon 20 insertion−mutant NSCLC who had received 1–2 prior lines of chemotherapy and administered T−DM1 (3.6 mg/kg every 21 days), resulting in an objective response rate(ORR) of 38.1% (90% CI: 23.0–55.9%), a median duration of response(mDOR) of 3.5 months, median progression−free survival(mPFS) of 2.8 months, and median overall survival(mOS) of 8.1 months. In the phase II study (96) of trastuzumab emtansine (T-DM1) for 49 pretreated patients with advanced HER2-overexpressing NSCLC (29 IHC 2+ and 20 IHC 3+), an ORR of 20% (consisting of 4 partial responses lasting 2.9 to 10.8 months) was confined to the IHC 3+ cohort, with no significant survival difference between cohorts.

Trastuzumab deruxtecan (T-DXd) is composed of a humanized anti-HER2 IgG1 antibody, a cleavable tetrapeptide-based linker, and topoisomerase I inhibitor payload (100). Early phase I study investigations demonstrated substantial activity, with an ORR of 72.7% and mPFS of 11.3 months in a cohort of 11 patients with HER2-mutant NSCLC (101). The phase II DESTINY-Lung01 trial (a single-arm, phase 2 trial, NCT03505710) (N = 91) established an ORR of 55% with mPFS and overall survival (OS) of 8.2 and 18.6 months, respectively (70, 102, 103). DESTINY-Lung02(phase II trial, NCT04644237) further confirmed dose-dependent efficacy: ORRs were 49.0% (5.4 mg/kg, N = 102) and 56.0% (6.4 mg/kg, N = 50), with corresponding mPFS of 9.9 and 15.4 months, however, the higher dose was associated with increased toxicities—notably ILD—leading to the establishment of 5.4 mg/kg as the recommended standard dose in clinical practice. The 5.4 mg/kg dose exhibited a more favorable safety profile while maintaining substantial intracranial activity (intracranial ORR 25.0%) (104). These findings underscore the critical role of dose optimization in balancing the remarkable efficacy of T-DXd against its dose-limiting toxicities, particularly ILD. The 5.4 mg/kg regimen represents a refined risk-benefit profile for this patient population. In the Chinese subset analyzed in DESTINY-Lung05(NCT05610686) (N = 72), the ORR reached 58.3%, with a 12-month PFS rate of 55.1% (93).

Trastuzumab rezetecan (SHR-A1811) received approval from the National Medical Products Administration (NMPA) of China in May 2025 for the treatment of previously-treated, HER2-mutant, unresectable locally advanced or metastatic NSCLC (81). In the HORIZON-Lung study(phase 2, single-arm study, NCT04818333) (N = 94), an ORR of 73% was observed; however, hematologic toxicities were frequently reported, including grade 3–4 neutropenia (40%), leukopenia (27%), and thrombocytopenia (11%) (105, 106).

Disitamab vedotin (RC48), already approved in China for HER2-overexpressing gastric cancer, shows expanding clinical applications (79). Among 22 patients with HER2-positive NSCLC, the overall ORR was 45.5% with mPFS of 7.5 months. Subgroup analyses revealed differential efficacy across treatment regimens: RC48 monotherapy yielded an ORR of 47.7% and mPFS of 8.1 months; combination with HER2-TKIs resulted in an ORR of 50.0%; whereas the triplet regimen of RC48 plus platinum-based chemotherapy and bevacizumab achieved a markedly higher ORR of 71.4% (107).

The phase II trial represents the first report on the efficacy and safety of the bispecific HER2-directed antibody-drug conjugate TQB2102 in the neoadjuvant setting for HER2-positive breast cancer, demonstrating both robust antitumor activity and a manageable safety profile (108). Separately, preclinical studies support the antitumor potential of other HER2-targeted ADCs— including A166, and ARX788—in HER2-positive models, though clinical validation in advanced NSCLC remains under investigation (101, 109–115).

TROP2, a transmembrane glycoprotein involved in the regulation of cell proliferation, is broadly expressed throughout the respiratory epithelium (116). Its overexpression is correlated with elevated cancer-specific mortality in lung adenocarcinoma, mediated through enhanced proliferative signaling, increased invasive capacity, metastatic competence, and resistance to immunotherapy (117–120). Currently, three TROP2-targeting ADCs—Datopotamab deruxtecan (Dato-DXd), Sacituzumab ovitecan (SG), and Sacituzumab tirumotecan (Sac-TMT)—are under clinical evaluation or use in NSCLC.

Dato-DXd consists of a humanized anti-TROP2 IgG1 monoclonal antibody conjugated to Deruxtecan, a potent topoisomerase I inhibitor, via a plasma stable, tetrapeptide-based linker. This design enables targeted payload release upon lysosomal proteolytic cleavage, minimizing systemic exposure and off-target toxicity (120). In the TROPION-PanTumor 01 trial(NCT03401385) (N = 210), patients with unresectable advanced/metastatic NSCLC treated with Dato-DXd achieved an ORR of 26%, with a median duration of response (mDOR) of 10.5 months, mPFS of 6.9 months, and mOS of 11.4 months (116). The TROPION-PanTumor 02 study(NCT05463060), a Phase 1/2 trial in Chinese patients with advanced solid tumors, reported an ORR of 45.0% and a disease control rate (DCR) of 85.0% in the NSCLC cohort (n=40), with mDOR of 8.3 months (121, 122). In the TROPION-LUNG01 trial (NCT04656652), Dato-DXd demonstrated a numerical but non-significant improvement in mPFS compared with docetaxel (4.4 vs. 3.7 months; HR = 0.89) in patients with previously treated advanced NSCLC (123). The TROPION-LUNG05 study(NCT04484142) (N = 137) further reported an ORR of 35.8%, mDOR of 7.0 months, and disease control rate (DCR) of 78.8%, with consistent responses observed in the EGFR-mutant subgroup (ORR 34%) (124, 125).

Sacituzumab tirumotecan (Sac-TMT, also known as MK-2870/SKB264) is a novel TROP2-targeting ADC that, following internalization, releases a topoisomerase I inhibitor payload, resulting in DNA damage, cell cycle arrest, and apoptosis (126). Across multiple clinical trials, Sac-TMT has demonstrated consistent antitumor activity. In the phase 1/2 KL264–01 trial (NCT04152499), Sac-TMT demonstrated an ORR of 40% (17/43) and a mPFS of 6.2 months in 43 previously treated advanced NSCLC patients (34). In the phase 2 SKB264-II-08 trial (NCT05631262, N = 64) involving previously treated EGFR-mutant NSCLC patients, achieved an ORR of 34% (22/64) and a mPFS of 9.3 months (34). In the phase 3 OptiTROP-Lung04 trial(NCT05870319) (n=376) in EGFR-mutated NSCLC after EGFR-TKI failure, sac-TMT significantly improved mPFS (8.3 vs 4.3 months) and 18-month OS rate (65.8% vs 48.0%) compared to platinum-chemotherapy (80). In a head-to-head comparison with docetaxel for EGFR-mutant NSCLC, Sac-TMT demonstrated significant superiority across all efficacy endpoints: ORR (45% vs 16%), mPFS (6.9 vs 2.8 months), and 12-month OS rates (73% vs 54%)(NCT05631262) (127). These data support Sac-TMT as a promising therapeutic option, particularly for EGFR-mutant NSCLC.

Sacituzumab govitecan (SG, IMMU-132) employs a hydrolysable linker to conjugate the anti-TROP2 antibody with SN-38, the active metabolite of irinotecan, enabling localized drug release both intracellularly and within the tumor microenvironment (67, 128). The membrane-permeability of SN-38 also facilitates a potent bystander effect, broadening its applicability across heterogeneous tumors (129, 130). The open-label, phase III EVOKE-01(NCT05089734), which compared SG(n=299) to docetaxel(n=304) in previously treated advanced NSCLC, SG showed numerical but non-significant improvements in mOS (11.1 vs. 9.8 months) and mPFS (4.1 vs. 3.9 months) (131). Although the primary endpoint was not met, SG exhibited a trend toward survival benefit and a more favorable tolerability profile. In the phase 2 TROPiCS-03 study(NCT03964727) evaluating SG as second-line therapy in 43 extensive-stage SCLC (ES-SCLC) patients, the ORR was 41.9% among 43 evaluable patients, with a median duration of response of 4.73 months, mPFS of 4.40 months, and mOS of 13.60 months (132). Several other TROP2-targeting ADCs, such as SHR-A1921, BL-M02D1, and LCB84 are ongoing clinical trials for NSCLC (133, 134), and the research results are worthy of continuous attention.

c-MET, also known as hepatocyte growth factor receptor (HGFR), is overexpressed frequently in solid tumors, including NSCLC, rendering it a promising target for the development of anticancer therapeutics (35, 135–137). Telisotuzumab vedotin (Teliso-V; ABBV-399), the first c-MET-targeting ADC approved for advanced NSCLC, comprises a humanized anti-c-MET mAb (telisotuzumab) site-specifically conjugated to the potent microtubule inhibitor MMAE via a protease-cleavable valine-citrulline dipeptide linker (61, 138, 139). Consistent antitumor activity of Teliso-V has been demonstrated across multiple clinical trials in NSCLC. In a phase I/II study (NCT02099058) evaluating Teliso-V combined with erlotinib in 42 c-MET-positive NSCLC patients, the efficacy-evaluable population (n=36) achieved an ORR of 30.6%, DCR of 86.1%, and mPFS of 5.9 months. The EGFR-mutant subgroup (n=28) showed comparable efficacy, with an ORR of 32.1%, DCR of 85.7%, and mPFS of 5.9 months (140). Another trial (NCT02099058.) (n=52) revealed that among 40 response-evaluable patients with c-Met-overexpressing NSCLC, Teliso-V monotherapy yielded an ORR of 23%, with median duration of response of 8.7 months and mPFS of 5.2 months (141). The LUMINOSITY trial (NCT03539536), which specifically enrolled patients with advanced c-MET-overexpressing NSCLC (n=172) who had received ≤2 prior lines of therapy, reported an ORR of 28.6%, a median duration of response of 8.3 months, mOS of 14.5 months, and mPFS of 5.7 months (142). These consistent response rates across heterogeneous NSCLC populations confirm the meaningful clinical activity of c-Met-directed therapy in this setting.

The therapeutic landscape for c-MET-positive solid tumors continues to expand with the emergence of numerous c-MET-targeting ADCs. Preclinical candidates currently under investigation include STI-D0602, hucMet27-based ADCs, cIRCR201-dPBD, P3D12-vc-MMAF, LAV- and HAV-ADCs, PCMC1D3-Duocarmycin SA, as well as c-Met/EGFR bispecific constructs. Meanwhile, several agents have advanced into clinical evaluation, such as SHR-A1403, TR1801-ADC, RC108, BYON3521, MYTX-011, ABBV-400, REGN5093-M114, and AZD9592, persistent and growing interest in c-MET as a therapeutic target (143–146).

HER3 is broadly expressed in NSCLC and has emerged as a promising therapeutic target. The HER3-targeting ADC Patritumab deruxtecan (HER3-DXd) has shown substantial efficacy in patients with EGFR-mutated NSCLC following progression on EGFR-TKI and platinum-based chemotherapy. Initial phase I U31402-A-U102 trial (NCT03260491) results showed a confirmed ORR of 41%, with mPFS of 6.4 months and mOS of 16.2 months (147). These findings of this phase II study HERTHENA-Lung01(NCT04619004) enrolled 225 patients with advanced EGFR-mutated NSCLC previously treated with EGFR-TKIs therapy and platinum-based chemotherapy, demonstrated a confirmed ORR of 29.8%, median duration of response of 6.4 months, mPFS of 5.5 months, and mOS of 11.9 months in a comparable patient population (30). The consistent therapeutic activity observed across these studies underscores the clinical potential of HER3-DXd in this treatment-resistant NSCLC subgroup.

CEACAM5, a glycosylphosphatidylinositol-anchored membrane glycoprotein frequently overexpressed in NSCLC, plays a key role in intercellular adhesion, proliferative signaling, tumor invasion, and resistance to apoptosis (148, 149). Preclinical studies have demonstrated that CEACAM5-targeted ADCs potently suppress tumor growth in CEACAM5-positive lung cancer models (50, 150, 151).

B7-H3, a member of the B7 costimulatory family, is commonly overexpressed on tumor cells and tumor-associated vascular endothelium in NSCLC and is correlated with poor prognosis (152–154). The B7-H3–targeting ADC ifinatamab deruxtecan (I-DXd), which delivers a topoisomerase I inhibitor, has shown encouraging efficacy in early clinical trials involving pretreated extensive-stage small cell lung cancer (SCLC). Treatment with I-DXd resulted in an ORR of 54.8%, a mPFS of 5.5 months, and a mOS of 11.8 months. Notably, substantial intracranial activity was observed, with a central nervous system–confirmed response rate of 37.8% (154, 155).

ADCs have transformed the treatment landscape for advanced non-small cell lung cancer through their unique precision-targeted delivery mechanism. With the ongoing development of ADCs targeting a growing array of antigens—including HER2, TROP2, c-MET, HER3, CEACAM5, and B7-H3, as well as emerging ones like EGFR (to overcome resistance), DLL3 (in SCLC), FRα, and NECTIN4—this therapeutic class is increasingly positioned as a cornerstone strategy to overcome tumor heterogeneity and treatment resistance in NSCLC. (Figure 3).

The distinct clinical profiles of ADCs targeting the same antigen arise from deliberate design choices. For HER2, the superior efficacy of T-DXd (high-DAR, cleavable linker, membrane-permeable DXd payload) in HER2-mutant NSCLC is counterbalanced by its ILD risk, whereas T-DM1 (lower DAR, non-cleavable linker, DM1) shows modest activity and a different toxicity spectrum. For TROP2, Dato-DXd and sac-TMT employ different linker-topoisomerase I inhibitor systems, correlating with varied ILD rates and subtype efficacy; SG’s hydrolyzable linker and SN-38 payload underlie its pronounced hematologic and gastrointestinal toxicities. For c-MET, Teliso-V’s MMAE payload defines both its activity and neuropathy profile, while next-generation candidates (e.g., ABBV-400) are exploring alternative payloads (e.g., topoisomerase I inhibitors) to improve the therapeutic index. Thus, antibody affinity, linker stability, payload mechanism, and DAR collectively dictate an ADC’s efficacy-toxicity balance, guiding their optimized use in NSCLC.

ILD/pneumonitis is a serious and potentially fatal complication associated with ADC therapy in advanced NSCLC (119, 159). The reported incidence of ILD varies considerably across studies, depending on trial design, dosing regimen, and patient baseline characteristics. T-DXd demonstrates all-grade ILD in 11–28% of patients, with ≥Grade 3 events occurring in 2–7%, including fatal (Grade 5) cases in 2% (101, 101, 104, 160). Dato-DXd demonstrates all-grade ILD incidence of 6–9%, with ≥Grade 3 events in 2–3.6% (including 0.7% Grade 5) (102, 122–125, 161–163). Trastuzumab Rezetecan exhibits all-grade ILD in 10% of patients (≥Grade 3: 5%) (81, 105, 111), while SG demonstrates 5–10% all-grade and 2–3% ≥Grade 3 incidence (67, 131, 132).HER3-DXd reports all-grade ILD in 5–29%, with ≥Grade 3 events in 1–2.4% (including 1–2.4% Grade 5) (30, 164, 165). SHR-A1811 demonstrates ≥Grade 3 ILD in 2% (including one Grade 5 case) (114) and sac-TMT shows the lowest all-grade incidence at 1–2% (34, 127).

Early recognition and prompt corticosteroid intervention are critical for ILD management. Upon radiographic or clinical suspicion, ADC therapy should be immediately suspended with concurrent exclusion of infection. Grade 1 ILD necessitates temporary drug discontinuation and short-course corticosteroids (prednisone ≥0.5 mg/kg/day), with therapy resumption only after complete resolution. For Grade ≥2 ILD, permanent drug discontinuation and immediate high-dose corticosteroids (prednisone/methylprednisolone ≥1 mg/kg/day) are mandatory, followed by gradual tapering over ≥4 weeks. Severe or progressive cases require hospitalization and multidisciplinary pulmonary consultation. Baseline and serial high-resolution computed tomography monitoring—particularly during the initial six months—is recommended for early detection and improved outcomes (166, 167).

Hematologic adverse events represent another major toxicity category in advanced NSCLC, with neutropenia, anemia, and thrombocytopenia being most prevalent. Neutropenia incidence ranges from 20–79% (all-grade) and 1–58% (≥Grade 3), with the highest rates observed for trastuzumab rezetecan (55% all-grade; 40% ≥Grade 3) and SG (52–79% all-grade; 28–58% ≥Grade 3) (105, 114, 122, 124, 125, 131, 132, 160, 161, 168). Anemia occurs in 30–60% (all-grade) and 4–24% (≥Grade 3) of patients, with T-DXd showing the highest incidence (48–60% all-grade; 8–16% ≥Grade 3) (30, 114, 125, 160, 161). Leukopenia affects 32–45% (all-grade) and 4–27% (≥Grade 3), while thrombocytopenia occurs in 20–28% (all-grade) and <1–29% (≥Grade 3) of patients, with HER3-DXd demonstrating the highest severe thrombocytopenia rate (21–29%) (34, 105, 122, 124, 125, 127, 160, 161, 168).

These hematologic toxicities are generally reversible through dose modification and supportive measures. Routine complete blood count monitoring before each treatment cycle enables early detection. For Grade ≥3 neutropenia or thrombocytopenia, temporary drug interruption until recovery to Grade ≤2 is recommended, followed by dose reduction or interval extension upon reinitiation. Granulocyte colony-stimulating factor (G-CSF) prophylaxis or treatment should be considered for prolonged neutropenia. Anemia management includes transfusion support or treatment delay, while platelet transfusion is reserved for severe thrombocytopenia or bleeding risk. Most events resolve with these interventions, with permanent discontinuation rarely required (162, 166, 169, 170).

Gastrointestinal adverse events are frequently observed with ADC therapy in NSCLC. Nausea represents the most common all-grade event (37–65%), with incidence highest for SG (58–65%) and T-DXd (52–62%); ≥Grade 3 nausea occurs in 1–14%, most frequently with HER3-DXd (14%). Vomiting affects 20–42% of patients (all-grade) and 0–2% (≥Grade 3). Decreased appetite occurs in 20–48% (all-grade) and 5–19% (≥Grade 3), while diarrhea demonstrates the widest incidence range (4–64% all-grade), with SG showing the highest rates (59–64% all-grade; 7–13% ≥Grade 3) (30, 105, 111, 122, 125, 160–162, 164, 168).

Gastrointestinal toxicity induced by ADCs are common dose-limiting toxicities in patients with NSCLC. Management focuses on minimizing treatment interruptions while maintaining quality of life through prophylactic measures, individualized interventions, and multidisciplinary collaboration. Primary approaches include antiemetics, fluid replacement, and antidiarrheal agents tailored to symptom severity.

Fatigue represents the most prevalent general toxicity, affecting 20–56% of patients across ADC classes (all-grade) and 2–12% (≥Grade 3) (162). Alopecia occurs in 18–42% of patients, exclusively Grade 1–2 (105, 111, 122, 125, 160, 161, 163). Stomatitis/oral mucositis affects 49–60% of patients (all-grade), with ≥Grade 3 events in 7–9.5%, primarily associated with Dato-DXd (30, 122, 125, 161, 163). Notable class-specific toxicities include peripheral neuropathy with Teliso-V (42–57% all-grade; 7–≥20% ≥Grade 3) (61, 140–142), ocular events with A166 (corneal epithelial disease: 30.9%; blurred vision: 18.5%) (115), peripheral edema with telisotuzumab vedotin (≥20% all-grade) (140–142), and abdominal pain with HER3-DXd (≥10% all-grade) (30).

Despite demonstrating remarkable efficacy in advanced NSCLC, ADC-based therapeutics face several significant challenges. First, substantial heterogeneity in the expression of key targeted antigens—such as HER2, TROP2, and HER3—across patient populations often limits clinical benefit in certain individuals (113, 171, 172). Second, the lack of standardized methodologies for biomarker assessment introduces potential biases in patient selection and stratification (24). Furthermore, suboptimal tumor penetration and blood-brain barrier crossing significantly compromise effective ADC delivery (164, 173, 174).

Resistance remains a significant challenge for ADC therapy in NSCLC, involving multi-step mechanisms spanning from target recognition to intracellular cytotoxicity. Key pathways include: antigen downregulation or spatial heterogeneity (e.g., reduced HER2/TROP2 expression), which directly impairs ADC binding (175, 176); altered internalization pathways (such as a shift toward caveolin-1-mediated uptake) and lysosomal dysfunction (e.g., SLC46A3 deficiency), which hinder payload release (177, 178); overexpression of ATP-binding cassette (ABC) transporters (e.g., ABCB1, ABCC1/2), a well-documented mechanism of payload efflux validated in multiple ADCs including T-DM1 and T-DXd (179); and linker instability leading to premature systemic cleavage, which reduces effective drug concentration at the tumor site (180). Collectively, these layered resistance pathways represent a major obstacle to durable clinical responses with ADC-based treatments in NSCLC.

In terms of safety, despite their targeted design, ADCs still exhibit off-target effects and premature payload release, leading to toxicity profiles that partially resemble conventional chemotherapy (158). Notably, respiratory toxicities—especially ILD and pneumonitis—represent the most serious dose-limiting adverse events, with particularly high incidence observed with T-DXd and Dato-DXd (100, 101, 168). Linker instability and elevated drug-to-antibody ratios may contribute to molecular aggregation and altered pharmacokinetics, thereby narrowing the therapeutic window (15, 22, 109, 181, 182). Importantly, the frequent presence of underlying pulmonary impairment in advanced NSCLC patients exacerbates susceptibility to ILD and further constrains safe dosing parameters (24, 52). Concurrently, tumor cells employ diverse resistance mechanisms, including antigen downregulation, impaired internalization, lysosomal dysfunction, and upregulation of drug efflux pump, collectively undermining ADC therapeutic efficacy (22, 183, 184) (Figure 5).

Thus, a paramount clinical challenge is how to concurrently overcome therapeutic resistance and manage unique toxicities to maintain a favorable therapeutic window for ADC therapy in advanced NSCLC.

To systematically overcome these challenges, a multi-tiered strategic framework is essential. For optimized patient selection, developing dynamic and robust biomarker systems that integrate multi-omics profiling (26, 84, 185, 186), artificial intelligence-assisted radiomics, liquid biopsy applications, and advanced molecular imaging technologies will enable precise patient stratification and treatment tailoring (102, 187–189). In drug design, focused development of next-generation targets and innovative structural configurations—including bispecific antibodies and dual-payload ADCs—can facilitate simultaneous engagement of multiple antigens or signaling pathways, thereby better addressing tumor heterogeneity and resistance mechanisms (190, 191). Looking ahead, newly emerging next-generation ADCs strategies hold substantial promise for further enhancing therapeutic efficacy, widening the therapeutic window, and overcoming persistent limitations such as resistance, heterogeneity, and off-target toxicity. Novel linker–payload systems with superior circulatory stability and tumor-selective release, incorporating traceless or hydrophilic linkers paired with diversified payloads (e.g., topoisomerase I inhibitors, DNA alkylators, microtubule disruptors, or immunomodulatory agents) to improve intracellular delivery and bystander effects (192, 193). Optimized DAR enabled by precise site-specific conjugation technologies, producing homogeneous ADCs with balanced loading, favorable pharmacokinetics, and reduced nonspecific toxicity (194). Conditionally activatable ADCs (e.g., probody-drug conjugates or pH/protease-sensitive masked constructs) that remain inert in normal tissues but activate selectively in the tumor microenvironment, thereby minimizing on-target off-tumor toxicity (146, 192, 195). Emerging preclinical modalities such as immunostimulatory ADCs (ISACs) delivering innate immune agonists to elicit antitumor immunity, and degrader-antibody conjugates (DACs) incorporating PROTAC-like mechanisms for catalytic degradation of oncogenic proteins, providing amplified potency and resistance mitigation (195, 196). Collectively, these advancements are poised to markedly broaden the clinical applicability of ADCs across a wider range of NSCLC. Regarding therapeutic strategies, rational combination regimens incorporating immune checkpoint inhibitors or EGFR-TKIs may generate synergistic antitumor activity while delaying the emergence of resistant clones (174, 197, 198). Additionally, continuous optimization of antibody affinity, linker stability, and payload delivery efficiency remains crucial for enhancing the overall therapeutic performance of ADCs.

In summary, through systematic integration of these multidimensional strategies, current limitations in ADC therapy for NSCLC can be progressively addressed, ultimately providing patients with more precise, effective, and durable treatment options (Figure 6).