Combining antibody-drug conjugates with immune checkpoint inhibitors: A new paradigm for breast cancer therapy.

Background: Antibody-drug conjugates (ADCs) target cytotoxic payloads like microtubule and topoisomerase I inhibitors to the tumor, thereby inducing selective tumor cell death. ADCs can also trigger anti-tumoral immune responses via induction of immunogenic cell death (ICD). Recent advances in treatment of urothelial cancer demonstrate the high potential of ADCs, e.g. also in combination with PD-(L)1 immune checkpoint inhibitors (ICI). However, significant challenges still remain such as (partial) non-response, high relapse rates and notable toxicity, all highlighting the need to further improve the treatment. GDF-15 acts as a local immunosuppressant, disrupting immune cell infiltration and inhibiting myeloid cell differentiation. GDF-15 blockade in anti-PD1/PD-L1 relapsed/refractory, last-line cancer patients has shown durable anti-tumor responses when combined with PD-1 ICI (NCT04725474). Beyond tumoral overexpression, GDF-15 is also induced by various chemotherapeutic agents. Whether GDF-15 is induced by ADC payloads and could mediate resistance to therapy is currently unknown. Here, we investigated if ADC treatment can induce GDF-15 release from tumor cells and if GDF-15 neutralization may enhance ADC activity. Methods: Human tumor cell lines were treated with ADCs or unconjugated payloads. Cell viability, induction of ICD, and GDF-15 levels were measured in vitro by quantifying intracellular ATP, ecto-Calreticulin (ecto-CRT), and release of HMGB1, extracellular ATP (eATP), and GDF-15 in cell culture supernatants, respectively. Induction of tumoral and serum GDF-15 levels by ADCs was assessed in vivo using xenograft tumor models. The effect of GDF-15 neutralization on the anti-tumoral activity of ADCs was evaluated in syngeneic tumor models by monitoring tumor growth and animal survival. Results: ADCs and unconjugated payloads (MMAE, SN-38, calicheamicin, and PBD dimers) induced concentration-dependent lysis of tumor cells, releasing eATP and HMGB1 and translocating ecto-CRT, indicative of ICD induction. Concomitant with cell death, ADCs and their payloads induced GDF-15 release from tumor cells in vitro. ADC-induced GDF-15 release was confirmed in vivo by increase in tumoral and circulating GDF-15 levels in human tumor xenografted mice. Lastly, combining anti-GDF-15 with ADC treatment improved tumor growth delay markedly in a syngeneic tumor model, accompanied by enhanced immune cell infiltration and activation. Conclusion: ADC treatment induces GDF-15 which contributes to reduction of ADC activity. Blockade of GDF-15 enhances ADC activity and immune cell number and activation in the tumor. Therefore, GDF-15 blockade may hold significant potential as therapeutic strategy to enhance ADC activity in cancer patients. Citation Format: Neha Vashist, Daniel Schätzlein, Amelie Köhler, Sabrina Genssler, José Medina-Echeverz, Eugen Leo, Thorsten Ross, Christine Schuberth-Wagner. GDF-15 neutralization enhances the therapeutic activity of antibody-drug conjugates [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 4777.

Introduction: Antibody-drug conjugates (ADCs) have become a key part of metastatic breast cancer (MBC) treatment. Trastuzumab deruxtecan (T-DXd), and Sacituzumab Govitecan (SG) are approved ADCs available for the treatment of MBC. Completed trials that led to the approval of these ADCs did not include patients who had received the other ADC as prior therapy. Little is known about the optimal sequencing of these agents and how clinicians are incorporating ADC sequencing decisions at bedside. Methods: An online survey regarding the use of sequential ADCs was distributed electronically from April 2023 to July 2023 among US clinicians who treat patients with breast cancer. The survey included eight questions assessing clinician practice settings and the use of ADC sequencing and five case-based scenarios (table 1). Descriptive statistics were used to assess survey responses. Results: 107 survey responses were received, out of which 72% were female responders and 93% were medical oncologists. The majority of responders practiced in an academic setting (83%) and reported being involved in clinical research (82%). 58% of responders have been in practice for >10 years and 68% treat >20 breast cancer patients per week. 87% had prescribed an ADC post-ADC for MBC. 46% of responders thought that the degree of benefit for an ADC post-ADC would be similar to the benefit noted in the pivotal ADC trials, and 54% thought that the degree of benefit with sequencing would be lower than in the pivotal trials. Regarding the case-based questions for patients with triple-negative breast cancer and HER2 low disease who had disease progression on first-line metastatic therapy, 64-71% of clinicians opted to give SG as the first ADC followed by T-DXd as the second ADC in sequence, regardless of age, PDL1 status and prior metastatic therapies. For a patient with hormone-positive (HR+), HER2 low MBC, who had received capecitabine as the first metastatic chemotherapy, 50% opted to give T-DXd as the first ADC followed by SG as the second ADC, and 40% opted to give weekly paclitaxel followed by SG as the first ADC. For a patient with HR+, HER2 low MBC who had received two prior chemotherapies for metastatic disease, 77% opted for T-DXd as the first ADC, followed by SG as the second sequential ADC. When grade 1 pneumonitis was added as a comorbidity to the case, only 16% opted to give T-DXd as the first ADC choice. Conclusion: Almost 90% of clinicians report prescribing sequential ADCs for MBC, yet there is little uniformity in how these ADCs are sequenced. More than 50% felt that the benefit of the second ADC in the sequence will be lower than the registration trials that led to the approval of the ADC in a setting of no prior ADC treatment. The optimal sequencing of ADCs remains an area of unmet need and further studies are needed to guide optimal medical decisions regarding sequential ADC-based treatment algorithms for patients with MBC. Table 1. Case-based scenarios for ADC sequencing Citation Format: Yara Abdou, Prarthna Bhardwaj, Rachel Abelman, Laura Spring, Aditya Bardia, Lisa Carey, Priyanka Sharma. Practice patterns for sequential use of antibody-drug conjugate after antibody-drug conjugate in metastatic breast cancer: results from a physician survey [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO3-05-14.

Antibody–drug conjugates (ADCs) are a promising cancer therapy for targeted delivery of drugs to tumor cells. However, resistance to ADCs remains a challenge, necessitating the exploration of combination therapies. A strong biological theory suggests that ADCs interact with cancer cells and immune cells by triggering mechanisms such as immunogenic cell death, dendritic cell activation, and memory T-cell activation, resulting in long-term anti-tumor immunity and ultimately potential synergistic effects with immunotherapy. Based on extensive and reliable preclinical data, several clinical trials are currently combining ADCs with immune checkpoint inhibitors (ICIs) for the treatment of various cancers, including breast, gastric, and non-small-cell lung cancers, to evaluate the safety and anti-tumor activity of the combination therapy. Preliminary evidence from early clinical trials has reported more effective efficacy data. This paper reviews the combination of ADCs and immunotherapy, highlights the key mechanisms by which the two act synergistically, and summarizes the available clinical evidence against different ADCs targets. The paper also explores the re-challenges used for combination therapies and optimized design options for ADCs drugs.

Combining antibody-drug conjugates with immunotherapy in solid tumors: current landscape and future perspectives

Background: Antibody-targeted amanitin conjugates (ATACs) are a new class of antibody-drug conjugates (ADCs) using amanitin as a toxic payload. Amanitin binds to the RNA polymerase II and thereby efficiently inhibits the cellular transcription process. The present study highlights the benefit of combining ATACs with immune checkpoint inhibitors. The combination of these two modalities leads to an induction of immunogenic cell death (ICD) in vitro and a synergistic anti-tumor effect in vivo. Hence, the combination of ATACs with immune checkpoint inhibitors (ICI) provides a promising approach for potential further cancer treatment. Material and methods: Cell lines: BT-474 (breast ductal carcinoma); BJAB, Raji, (Burkitt lymphoma) Antibody: engineered monoclonal antibody produced at Heidelberg Pharma Toxic warhead: Cysteine reactive amanitin-linker constructs were synthesized at Heidelberg Pharma and conjugated site-specifically to the antibody. Animal models: Raji cells with/without human peripheral blood mononuclear cells (PBMCs) were implanted subcutaneously in mice. Treatment: ADC (ATAC): single dose i.v.; immune checkpoint inhibitor: Q3D x6. Results: The treatment of target-positive cell lines (e.g., BT-474 and BJAB) with corresponding ATACs led to the induction of three ICD hallmarks in vitro. In addition to increased surface expression of calreticulin (CRT), ATAC-treated tumor cells secreted adenosine triphosphate (ATP) and released high-mobility group box 1 protein (HMGB1). In contrast, this was not observed when the same cells were treated with a non-targeting ATAC. In a subcutaneous CDX model, mixed with human PBMCs, the combined administration of target specific ATACs with an immune checkpoint inhibitor led to an increased anti-tumor effect indicated by significant tumor growth inhibition as compared to single treatment with ATAC or ICI. This synergistic effect was not observed in mice bearing tumors without human PBMCs. Conclusions: Antibody-targeted amanitin conjugates (ATACs) induced immunogenic cell death in vitro and resulted in an increased anti-tumor effect in combination with an immune checkpoint inhibitor in a subcutaneous CDX model if human PBMCs were present. Consequently, the data presented provide a rationale to the use of ATACs in combination therapy with immune checkpoint inhibitors. Citation Format: Kristin Decker, Irina Dranova, Christian Orlik, Aniko Palfi, Christoph Mueller, Ram Kumar Singh, Robert Z. Orlowski, Torsten Hechler, Andreas Pahl, Michael Kulke. Combination of antibody-targeted amanitin conjugates (ATAC) with immune checkpoint inhibitors shows synergistic therapeutic effect in vitro and in vivo [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 921.

Use of antibody-drug conjugates (ADCs) is rapidly increasing in the field of oncology. While ADCs exhibit strong and cell-selective cytotoxicity, they do not show spatial selectivity. Near-infrared photoimmunotherapy (NIR-PIT, Alluminox™) utilizes photoactivatable ADCs, that is, antibody-photoabsorber conjugates (APCs). The photoabsorber used in NIR-PIT, IRDye700DX (IR700), is activated by light of ~690nm wavelength. APCs, usually administered by intravenous injection, bind to the target cell surface, and subsequent excitation-light illumination dramatically changes the status of IR700 from hydrophilic to hydrophobic, inducing aggregation of the APC-target molecule complex and cell burst. Dying cells release neoantigens as well as damage-associated molecular patterns, resulting in immunogenic cell death (ICD). Based on the favorable results of clinical trials, epidermal growth factor-targeted NIR-PIT has been performed in Japan since 2021 for patients with unresectable head and neck cancers (HNCs). Since pain and local edema are frequent adverse events (AEs), various measures have been taken against these AEs. Because NIR-PIT induces ICD, combining NIR-PIT with immune checkpoint inhibitor (ICI) therapy is thought to be a rather effective strategy. NIR-PIT could also locally destroy immune suppressor cells, such as regulatory T cells, in the tumor microenvironment. Currently, numerous clinical trials are under way to evaluate the efficacy of NIR-PIT as well as of combined NIR-PIT plus ICI therapy. In this review article, we describe the basics of NIT-PIT, results of translational experiments, current clinical application of NIT-PIT in HNCs, and relevant ongoing clinical trials.

Background: Amatoxin-based antibody-drug conjugates (ATACs) comprise a new class of antibody-drug conjugates (ADCs) using amanitin as a toxic payload. Amanitin binds to the RNA polymerase II and thereby efficiently inhibits the cellular transcription process. In the present study, we show that ATACs belong to the class of immune activating drugs which exhibit synergistic anti-tumor efficacy with immune checkpoint inhibitors (ICIs) in vivo by induction of immunogenic cell death (ICD). ICIs are a new class of cancer therapeutics utilizing patients` immune system to kill cancer cells. ICIs rely on the activity of the immune system to develop their full potential. Therefore, drugs that are heating up cold tumors and make them visible to the patients` immune system and by that enhancing the anti-tumor efficacy of ICIs, e.g., ATACs, are on high demand for the treatment of tumor patients. Material and methods: Cell line: Her2+ cell lines: NCI-N87; CD19+ cell line: Raji Antibody: anti-Her2 and anti-CD19 engineered monoclonal antibody produced at Heidelberg Pharma Toxic warhead: Cysteine reactive amanitin-linker constructs were synthesized at Heidelberg Pharma and conjugated site-specifically to the antibody. Animal models: Raji cells with human peripheral blood mononuclear cells (PBMCs), NCI-N87 cells or HCBx-10/HCBx-11 PDX (Xentech, France) tumor pieces were implanted subcutaneously in mice. Treatment: ATAC: single dose i.v.; immune checkpoint inhibitors: Q3Dx6 or Q3Dx5. Results: In vivo treatment of heterogenous Her2low PDX tumors with an anti-Her2-ATAC led to a significant tumor growth delay and complete tumor remission. Furthermore, increased expression of HMGB1 and surface exposure of calreticulin (CRT), two hallmarks of ICD, was observed in the same PDX tumors as well as in a Her2+ CDX (NCI-N87) tumor after the treatment with an anti-HER2 ATAC. In addition, the combined treatment of ATACs and different ICIs targeting CTLA-4 (Ipilimumab), PD-L1 (Pembrolizumab) or PD-1 (Avelumab) had a synergistic effect in a humanized lymphoma CDX model in the presence of human PBMCs. Combination treatment led to enhanced tumor growth inhibition and more tumor free animals as compared to single treatments with ATAC or ICI. Conclusions: The strong anti-tumor efficacy of ATACs even in heterogenous patient-derived xenograft models in combination with the induction of ICD in vitro and in vivo suggest that the anti-tumor effect of ATACs is accompanied by the activation of the immune system. This hypothesis is strengthened by the finding that ATACs and ICIs show a synergistic effect in vivo. The presented data highlights the general concept of the synergistic effect of ATACs and ICIs which applies to several types of ICIs thus strengthening the scientific rationale for combination treatments in clinical trials. Citation Format: Christian Orlik, Franziska Ebeling, Kristin Decker, Irina Dranova, Anikó Pálfi, Christoph Mueller, Torsten Hechler, Andreas Pahl, Michael Kulke. Amatoxin-based antibody-drug conjugates induce immunogenic cell death and improve the anti-tumor efficacy of immune checkpoint inhibitors in humanized mouse models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1754.

QUAD SHOT Radiotherapy and Doublet Immunotherapy in the Management of Anal Mucosal Melanoma: A Case Series of Efficacy and Toxicity of a Novel Treatment Approach and a Review of the Literature

The integration of antibody–drug conjugates (ADCs) with immune checkpoint inhibitors (ICIs) represents a paradigm shift in oncology, combining targeted cytotoxicity and adaptive immune activation to overcome resistance in refractory tumors. This review explores their mechanistic synergy, focusing on dual functions in reprogramming the tumor immune microenvironment. ADCs mediate antibody-dependent cellular cytotoxicity (ADCC), engaging NK cells and macrophages to release tumor-associated antigens (TAAs) and damage-associated molecular patterns. Immunogenic cell death (ICD) amplifies adaptive immunity by releasing TAAs for T-cell priming, while PD-L1 upregulation creates a targetable niche for PD-1/PD-L1 inhibitors. This strategy sustains interferon-γ signaling and drives effector T-cell differentiation, but overlapping immunostimulatory signals raise risks of cytokine release syndrome and immune-related adverse events, requiring biomarker-guided risk stratification. We propose a multidimensional immune microenvironment reprogramming framework, integrating tumor-infiltrating lymphocyte phenotyping, serum biomarkers, and spatial transcriptomic mapping, to optimize ADC–ICI therapy and balance efficacy with immunopathology.

Introduction: We report on the development and preclinical validation of NBE-002, a next-generation antibody drug conjugate (ADC) for the treatment of triple-negative breast cancer (TNBC). NBE-002 consists of a humanized monoclonal antibody directed against the receptor tyrosine kinase ROR1, expressed on the surface of numerous solid cancers including TNBC, and is site-specifically conjugated to a derivative of the highly potent anthracycline PNU-159682. Results: Therapeutic efficacy of NBE-002 was evaluated in ROR1-low/-intermediate/-high patient-derived xenograft (PDX) models of TNBC, lung adenocarcinoma, ovarian carcinoma, and a variety of sarcomas. NBE-002 was found to display significant anti-tumor activity in each indication. The most pronounced effect was achieved in TNBC, where complete tumor regression was observed already at the lowest ADC dose tested (0.33 mg/kg), even in models expressing low levels of ROR1 (H-score ≤70). Since these PDX studies were performed in immune-compromised hosts, and anthracyclines are known inducers of immunogenic cell death, anti-tumor activity was also investigated in syngeneic tumor models in immune-competent hosts. Anti-tumor activity of PNU-ADCs involved activation of the immune system, as shown by evaluation of NBE-002 or a Trastuzumab-PNU conjugate (T-PNU) in ROR1- or HER2-positive syngeneic breast cancer models, respectively. Depletion of CD8 T cells severely reduced anti-tumor activity, demonstrating an important role for T cells in driving tumor regression. Furthermore, when tumor free animals were re-challenged with the same tumor, tumor growth was inhibited in the absence of any further ADC administration, indicating the development of an immunological memory. Notably, combination of ADC and checkpoint inhibition, such as α-PD1 or α-CTLA4, significantly enhanced tumor eradication following the treatment. Conclusion: Our results demonstrate that NBE-002 is a highly effective and promising targeted therapeutic for the treatment of ROR1 positive TNBC and potentially other solid tumor indications that warrants clinical development. Considering the pronounced immune-modulatory functions of the PNU payload, NBE-002 may be particularly well suited for combination therapy with immune checkpoint inhibitors. NBE-002 is currently undergoing GMP manufacturing and initiation of clinical studies is expected in mid-2020. Citation Format: Roger R. Beerli, Lorenz Waldmeier, Rémy Gébleux, Francesca Pretto, Ulf Grawunder. NBE-002, an anthracycline-based immune-stimulatory antibody drug conjugate (iADC) targeting ROR1 for the treatment of triple-negative breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr LB-197.

For decades, chemotherapy has been the mainstay of breast cancer treatment. Novel therapies are expanding the therapeutic options and altering the treatment algorithms to manage this disease. The use and approval of immune checkpoint inhibitors (ICIs) and antibody-drug conjugates (ADCs) represent a few areas of progress. These therapies initially gained attention in the metastatic setting but have subsequently found a role in early-stage breast cancer. Although human epidermal growth factor receptor 2 (HER2) is at the center of ADC development, other surface antigens with a differential expression between tumor and normal cells may be appropriate for ADC targeting. This has led to the discovery of new ADCs targeting other receptors, including TROP-2, HER-3, and LIV-1, to name a few. Similarly, the addition of pembrolizumab in treating early-stage triple-negative breast cancer has led to exploring other ICIs in this setting. However, it has also raised important scientific questions regarding optimal patient selection, biomarkers that predict the success of ICIs, ideal chemotherapy partners, and the financial implications of bringing newer therapies to the forefront. In this review, we discuss the evolving landscape of ICIs and ADCs in managing early-stage breast cancer and provide an overview of potential future advancement in the field.

The treatment of cancer patients has dramatically changed over the past decades with the advent of monoclonal antibodies, immune-checkpoint inhibitors, bispecific antibodies, and innovative T-cell therapy. Antibody-drug conjugates (ADCs) have also revolutionized the treatment of cancer. Several ADCs have already been approved in hematology and clinical oncology, such as trastuzumab emtansine (T-DM1), trastuzumab deruxtecan (T-DXd), and sacituzumab govitecan (SG) for the treatment of metastatic breast cancer, and enfortumab vedotin (EV) for the treatment of urothelial carcinoma. The efficacy of ADCs is limited by the emergence of resistance due to different mechanisms, such as antigen-related resistance, failure of internalization, impaired lysosomal function, and other mechanisms. In this review, we summarize the clinical data that contributed to the approval of T-DM1, T-DXd, SG, and EV. We also discuss the different mechanisms of resistance to ADCs, as well as the ways to overcome this resistance, such as bispecific ADCs and the combination of ADCs with immune-checkpoint inhibitors or tyrosine-kinase inhibitors.

The use of immune checkpoint inhibitors in combination with chemotherapy for the treatment of triple-negative breast cancer is becoming more widespread as efficacy data accumulates. However, outcomes remain less than optimal and not all patients benefit from treatment. The aim of this article is to review the emerging chemoimmunotherapy strategies for triple-negative breast cancer. Searches were undertaken on Pubmed and Clinicaltrials.gov for relevant publications and trials. Preclinical and clinical data have provided insights into the differing immunomodulatory effects of chemotherapy agents, highlighting the immunostimulatory properties of anthracyclines. Mechanisms of resistance to immune checkpoint inhibition are discussed and the potential role of phosphatidylinositol 3-kinase (PI3K)/AKT and MAPK/ERK kinase (MEK) inhibitors in overcoming resistance. Finally, the emerging therapeutic class of antibody-drug conjugates for triple-negative breast cancer in combination with immune checkpoint inhibitors is reviewed. The type and sequence of chemotherapy agents play an important role in optimising the response to immune checkpoint inhibitors. Antibody-drug conjugates in combination with immune checkpoint inhibitors are a promising area of development.

1022 Background: Optimizing sequential use of Antibody Drug Conjugates (ADCs) is an area of unmet need and of rising clinical importance. With the recent approvals of sacituzumab govitecan (SG) for HR+/HER2- and triple negative metastatic breast cancer (MBC) as well as trastuzumab deruxtecan (T-DXd) for HER2-low MBC, many patients are now candidates for multiple ADCs. However, given potential cross-resistance based on antibody target vs payload (Coates et al, Cancer Discov. 2021), optimal sequencing remains uncertain. We evaluated the safety and efficacy of ADC after ADC for patients with HER2 negative MBC. Methods: We included all patients at an academic institution treated with more than one ADC for MBC. Each line of ADC beyond the first was evaluated for presence of the same “antibody target” or “payload” compared to prior ADC. Clinicopathological information was gathered by chart review. We defined “cross-resistance” as progressive disease (PD) at time of first restaging on second ADC. Progression-free survival (PFS) was evaluated as time from start of treatment to disease progression or death from any cause. All PFS estimation was done using the KM method. All pairwise comparisons across ADC were done using a Wilcoxon Rank Sum test to allow for divergences from normality in progression times. Significance was declared as a type I error less than 0.05. Results: A total of 193 patients with MBC were treated with ADCs between August 2014-February 2023. Among these,32 patients were identified as having received more than one ADC (HR+/HER2- = 13, TNBC = 19, HER2 low = 22). Median age at time of second ADC was 57.1 years (range 31.3-88.6) and patients had received a median of 4 lines (range 2-12) of prior treatment before initiation of second ADC. The median PFS on the first ADC used (ADC1) was significantly longer at 7.55 months (95% CI 3.22-10.25) compared to a median of 2.53 months on the second ADC (ADC2) (95% CI 1.38-4.14) (p=0.006). PFS for ADC2 with antibody target change was 3.25 months (95% CI 1.38 months, n/a) compared to 2.30 months with no target change (95% CI 1.38 months, n/a) (p=0.16). At time of first imaging, cross-resistance was present in 17 cases (53.1%), absent in 12 (37.5%), and not evaluable in 3 cases. When the second ADC contained the same antibody target as the first, cross-resistance was present in 9/13 cases (69.2%), compared to 8/16 cases (50.0%) when the second ADC targeted a different tumor antigen. Similarly, differences were noted based on payload switch vs not. Conclusions: This study highlights a subset that had cross-resistance to ADC after ADC, while others had durable responses on latter lines of therapy, particularly if a different antibody target was utilized. Further research is needed to validate these findings and discern mechanisms of clinical resistance to guide optimal sequencing of ADC-based treatment options.

BackgroundCancer immunotherapies that target immune checkpoints, such as immune checkpoint inhibitors (ICIs), antibody-dependent cellular cytotoxicity (ADCC), and antibody-drug conjugates (ADCs), have shown tremendous success in the treatment of solid tumors,...