腫瘤學創新浪潮再起！從科學突破到患者獲益，還要做對什么？專訪李敬博士 | Bilingual

2026年5月，美國FDA宣布批準Arvinas和輝瑞（Pfizer）公司聯合開發的蛋白降解靶向嵌合體Veppanu（vepdegestrant）上市，用于治療雌激素受體（ER）陽性、人表皮生長因子受體2（HER2）陰性、ESR1突變的經治晚期或轉移性乳腺癌成人患者。Arvinas公司的新聞稿指出，這是FDA批準的首款蛋白降解靶向嵌合體藥物。

這一里程碑發生之際，腫瘤學領域正經歷治療邊界的快速拓展。從靶向蛋白降解（TPD）、抗體偶聯藥物（ADC）等新興療法的興起，到合成致死機制與腫瘤微環境等機制研究的突破，創新浪潮正在重塑癌癥治療格局。

作為創新的賦能者，藥明康德依托一體化CRDMO平臺，為加速全球合作伙伴的腫瘤療法研發構建了一體化的能力，支持客戶早日將科學想法轉化為惠及患者的療法。

近日，藥明康德生物學平臺執行主任李敬博士接受了行業媒體Technology Networks專訪。作為親歷多輪腫瘤學創新浪潮的資深專家，李敬博士在專訪中探討了新興療法與機制突破如何驅動新一輪的腫瘤學創新，并推動科學發現轉化為具有臨床意義的療法。

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Technology Networks：從腫瘤學領域的幾次創新浪潮中，我們學到了什么？當前又有哪些科學轉變正在重新定義癌癥研究？

李敬博士：過去幾十年間，腫瘤領域經歷了多個具有變革意義的發展階段，例如激酶抑制劑、腫瘤免疫療法的興起。在我看來，這些突破共同推動腫瘤治療向更精準的方向演進。它們從根本上改變了癌癥治療模式，向著高度個體化、基于精準醫療的治療方案轉變，根據患者的腫瘤特性量身定制療法。

免疫檢查點抑制劑便是一個典型案例，該療法證明了我們能夠調動患者自身的免疫系統，實現傳統化療往往難以企及的長期緩解。

如今，ADC和T細胞銜接器（TCE）等新型療法同樣在持續發展。這些創新不僅持續深化對癌癥的科學理解，也重塑著未來的治療格局。

在新療法不斷涌現的同時，小分子藥物也在重新煥發活力。如今，小分子藥物仍是主流療法。共價修飾劑、蛋白-蛋白相互作用（PPI）抑制劑、蛋白降解劑和分子膠等新機制的不斷涌現，正在拓展小分子藥物的治療范圍，并重新激發業界對這一領域的關注。

Technology Networks：要使分子膠成為更加可靠、可重復的藥物發現引擎，需要具備哪些條件？該領域距離拐點還有多遠？

李敬博士：作為靶向蛋白降解劑的代表性類別，分子膠最初是在研究FK506、環孢素和雷帕霉素等天然產物的機制時被發現的。隨后，來那度胺（lenalidomide）成為首個在臨床上取得成功的分子膠降解劑。歷史上大多數分子膠都是偶然發現的，但這一局面正在迅速改變。

科學界意識到，誘導蛋白接近現象比此前認為的更為普遍。隨著高通量篩選（HTS）、親和質譜篩選（ASMS）和DNA編碼化合物庫（DEL）等篩選技術的進步，以及多樣性導向的化合物庫構建，針對特定靶點的分子膠理性發現正變得越來越有希望。由此，分子膠的藥物發現流程正朝著可規?；?、可重復性的方向轉變。

這些趨勢表明，分子膠領域正處于重要拐點。分子膠的研發正在回歸到更廣泛的鄰近藥理學框架中，即通過誘導蛋白質之間的鄰近關系來調控其功能。其應用范圍已超越蛋白降解，延伸至轉錄抑制、蛋白轉運和蛋白穩定性等多個方向。

▲分子膠苗頭化合物發現、表征及先導化合物優化的代表性工作流程

Technology Networks：ADC領域的下一個前沿是什么？還有哪些技術障礙有待突破？

李敬博士：ADC已成為腫瘤學中最活躍的方向之一。雖然連接子化學、載荷創新和靶點選擇等方面正在快速發展，但單一的技術突破并不足以推動ADC領域的整體進步。相反，真正驅動進步的，是多個領域進展的協同整合。

以ADC載荷為例，其范圍已從傳統的細胞毒性藥物，擴展至靶向特異性抑制劑、蛋白降解劑和免疫激動劑。目前，業界正向多載荷ADC和多特異性ADC的方向發展，以實現更精準的藥物遞送。這些新一代ADC的發展，將高度依賴結構創新和蛋白質工程的進步。其最終目標是更深入地理解ADC耐藥機制，并且更準確地預測聯合療法的療效持久性。

Technology Networks：合成致死呢？它是否可以成為一種適用于更多腫瘤類型的治療策略？

李敬博士：合成致死指的是兩個基因同時失活會導致細胞死亡，而其中任意一種失活則不會致死的遺傳現象?；诤铣芍滤涝黹_發的PARP抑制劑已經顯著改善了BRCA突變癌癥患者的預后。此外，多款針對MTAP缺失腫瘤的PRMT5抑制劑也已進入后期臨床開發階段。隨著遺傳依賴性圖譜的不斷擴展，合成致死有望在更廣泛的腫瘤領域發揮作用。

合成致死概念對癌癥治療極具吸引力，但其臨床成功仍面臨著障礙。一個主要挑戰在于，合成致死相互作用往往具有背景依賴性。雖然大規模篩選能產生大量候選靶點，但真正具有良好重復性、穩定性以及臨床相關性的合成致死基因對似乎并不多見。

合成致死療法的一個發展路徑，是將網絡生物學與機器學習相結合，以提高候選靶點優先級排序能力，提高識別穩定、具有轉化潛力的合成致死靶點的成功率。

Technology Networks：隨著腫瘤微環境研究的深入，哪些機制層面的發現正在轉化為切實可行的療法？又有哪些前沿進展具備轉化潛力？

李敬博士：腫瘤微環境的復雜性，使其成為腫瘤學研究最具潛力的領域之一，同時也是藥物開發中極具挑戰性的方向。

盡管如此，越來越多的科學洞見正逐步轉化為實際治療策略。例如，通過清除表達成纖維細胞活化蛋白的腫瘤相關成纖維細胞（FAP+ CAFs），能夠破壞腫瘤的纖維化基質結構，從而提高后續間皮素靶向CAR-T細胞療法和抗PD-1治療的敏感性。

與此同時，高分辨率數字病理學、空間轉錄組學和機器學習的進展，正在幫助研究人員以更高的精度描繪“熱”腫瘤和“冷”腫瘤的免疫圖譜。這些進展中涌現出良好的轉化潛力，多種靶向調節性T細胞（Tregs）、髓源性抑制細胞（MDSCs）、腫瘤相關巨噬細胞（TAMs）和腫瘤相關成纖維細胞（TAFs）的藥物已經進入臨床開發階段。此外，能夠同時調節腫瘤微環境內多條免疫抑制通路的聯合治療策略，有望成為克服免疫逃逸的關鍵突破口。

Technology Networks：早期整合生物標志物在現代腫瘤藥物開發中有多重要？哪些創新將持續變革癌癥治療的策略？

李敬博士：早期生物標志物，尤其是患者篩選生物標志物，一直是現代精準腫瘤學的重要組成部分。鑒于腫瘤的高度異質性，如果缺少基于生物標志物的患者分層，往往很難獲得具有臨床意義的治療應答率。

如今生物標志物的一個重要趨勢是，微小殘留病灶（MRD）檢測正從血液腫瘤迅速擴展至實體瘤。借助當前的技術平臺和嚴格的臨床驗證，基于循環腫瘤DNA（ctDNA）的MRD檢測能夠在癌癥治療的各個階段動態監測療效。

從更宏觀的領域來看，生物標志物正在經歷一項關鍵轉變：生物標志物策略正從靜態的預后標志物，轉向對兼具預測價值和可干預意義的生物信號進行動態、長期監測。

Technology Networks：藥明康德如何在保持深度生物學洞察的同時，以現代腫瘤藥物研發所需的速度推進項目？

李敬博士：在腫瘤藥物發現領域，速度至關重要。癌癥治療方案往往很復雜，而患者需求又十分迫切，因此研發效率始終是行業關注的重點。但速度并不意味著犧牲科學嚴謹性。在我們看來，保持科學研究的深度與按照行業所需速度推進項目，并不是一道選擇題。相反，兩者都是現代藥物研發的基本要求，而且必須同時實現。

實現這一平衡需要多維度能力的支撐，包括對因果生物學的深刻理解；持續洞察并預判新興科學趨勢和行業發展方向的能力；以及圍繞新型治療手段持續投入，構建相應的耐藥模型以及適配新作用機制的藥物反應研究體系。這些能力正是藥明康德搭建的一體化能力體系的組成部分。長期以來，藥明康德依托一體化賦能平臺，助力全球創新者加速腫瘤藥物的發現與開發。

展望未來，隨著近年來新興治療模式和作用機制的不斷涌現，將生物學發現轉化為具有臨床意義的治療獲益的能力正變得更強。例如，在研的新型非共價抑制劑daraxonrasib可與激活狀態下的野生型和突變型RAS蛋白（包括KRAS、HRAS和NRAS）結合，靶向治療RAS驅動腫瘤。近期公布的關鍵3期臨床研究結果顯示，在既往接受過治療的轉移性胰腺癌患者中，daraxonrasib治療組的中位總生存期（OS）達到13.2個月，而化療組僅為6.7個月。這是腫瘤學領域的一項重要突破。

▲用于KRAS靶點表征、作用機制研究及療效評價的代表性工作流程與檢測工具組合

這類突破正在改變過去數十年來腫瘤治療的臨床實踐，預示著未來創新療法將覆蓋更廣泛的適應癥，從而讓更多類型的癌癥患者從中獲益。

如今，腫瘤學創新正邁入全新的階段。在這一階段，新興治療模式、更深入的癌癥生物學認知以及先進的轉化研究工具正在加速融合，共同重塑藥物發現與開發的方式。從分子膠、ADC等治療模式，到合成致死、腫瘤微環境調控以及動態生物標志物策略，行業進展越來越依賴于將機制層面的生物學洞察與可規?；乃幬锇l現能力相結合。隨著這些科學創新不斷成熟，如何將對生物學機制的深入理解轉化為高效的研發執行能力，將成為推動更多精準、持久抗癌療法惠及患者的關鍵。

Inside the Next Wave of Oncology Innovation: How New Modalities and Cancer Biology Are Reshaping Therapeutics

On May 1, 2026, the US Food and Drug Administration (FDA) approved Veppanu (vepdegestrant) for adults with ER-positive, HER2-negative, ESR1-mutated advanced or metastatic breast cancer, marking the first approval of a drug based on proteolysis targeting chimeras. The approval comes at a time when oncology is witnessing a rapid expansion of therapeutic frontiers, from new modalities such as targeted protein degradation (TPD) and antibody-drug conjugates (ADC) to mechanistic advances in synthetic lethality and tumor microenvironment biology.

Dr. Jing Li, executive director at WuXi Biology, a segment of WuXi AppTec, who leads US teams to provide end-to-end biology services and solutions, has watched several waves of oncology innovation reshape the field over the course of his career. Recently, Technology Networks spoke with Li about how emerging modalities and mechanistic biology are driving the next wave of oncology and translating scientific discoveries into clinically meaningful therapies.

Innovative waves in oncology

What have we learned from transformative waves in oncology, and which scientific shifts are redefining cancer research today?

Over the past decades, the industry has navigated several transformative waves in oncology, such as kinase inhibitors and immuno-oncology. In Li’s opinion, these waves have driven oncology toward more precise therapies.

“These breakthroughs fundamentally shifted cancer therapy from a one?size?fits?all approach towards highly personalized, precision-based therapy tailored to each tumor’s unique profile.” Li stated that one prominent example is immune checkpoint inhibitors, which demonstrate that a patient’s own immune system can be harnessed to achieve durable, long?term remissions that conventional chemotherapy often cannot deliver.

Today, the field continues to advance modalities such as ADCs and T?cell engagers (TCEs). These innovations are redefining both scientific understanding of cancer and the future of treatment.

While new modalities are emerging, traditional small molecules are also gaining renewed momentum. As Li noted, they remain a powerful engine capable of revolutionizing medicine. Emerging modes of action such as covalent modifiers, PPI inhibitors, degraders, and molecular glues are expanding the therapeutic scope of small molecules and driving renewed industry interest in the modality.

Oncology research shifts:

• Oncology has shifted toward precision-based treatment guided by tumor biology.

• ADCs and TCEs are opening new therapeutic directions in cancer care.

• Novel small molecules are expanding the druggable space in oncology.

Inflection point for molecular glues

What would it take to make molecular glue a truly reliable, repeatable drug discovery engine, and how close is the field to the inflection point?

As a representative class of targeted protein degraders, molecular glues were first recognized while studying the mechanisms of natural products such as FK506, cyclosporin, and rapamycin. Later, Revlimid (lenalidomide) became the first clinically successful molecular glue degrader. As Li pointed out, most molecular glues were discovered serendipitously historically, but that paradigm is changing rapidly.

“Induced protein associations appear to be a far more common phenomenon than previously thought.Advances in diversity?oriented library synthesis and screening technologies, including HTS (high-throughput screening), ASMS (affinity selection mass spectrometry), and DEL (DNA-encoded library), are making rational discovery of molecular glues against intended targets increasingly feasible,”Li stated. “We are turning molecular glue discovery into a scalable and repeatable drug discovery process.”

▲Representative workflow for molecular glue hit identification, characterization, and lead optimization

In Li’s opinion, these trends suggest the field of molecular glues is at an inflection point. The concept of molecular glue is evolving into, or perhaps returning to, the broader framework of proximity pharmacology. This extends beyond protein degradation to include transcriptional repression, protein translocation, and protein stabilization.

Molecular glue momentum：

• Molecular glue identification is progressing from chance-based findings toward more intentional design.

• Chemically diverse compound libraries and advanced screening tools are helping make molecular glue programs more systematic and reproducible.

• The field is approaching a turning point, broadening from targeted degradation to wider proximity-driven mechanisms.

ADCs: Integration driving the next frontier

In the field of ADCs, what defines the next frontier, and which technical barriers still remain?

ADCs have become one of the most active areas in oncology. While the science of linker chemistry, payload innovation, and target selection is advancing rapidly, Li noted that no single innovation alone is sufficient to propel ADC research. Rather, progress is coming from the integration of advances across multiple areas.

Taking ADC payload as an example,the field has expanded beyond cytotoxic agents to include target?specific inhibitors, protein degraders, and immune stimulators. The field is moving toward multi?payload constructs and multi-specific ADCs to enable more precise delivery.Advancing these next-generation ADCs will depend heavily on structural innovation and protein engineering. Ultimately, the goal is to better understand ADC resistance mechanisms and improve the ability to predict combination strategies capable of producing durable responses.

ADC development drivers:

• ADC innovation depends on integrated progress across payloads, linkers, targets, and engineering design.

• New payload classes and more complex ADC formats are broadening the modality’s therapeutic potential.

• Deeper insight into resistance biology and combination strategies may support more durable ADC-based treatments.

Synthetic lethality: From PARP to broader application

What will it take for synthetic lethality to become a broadly applicable therapeutic strategy across tumor types?

Synthetic lethality describes a genetic interaction in which the loss of two genes causes cell death, while the loss of either gene alone is tolerated. Based on synthetic lethality, PARP inhibitors have transformed outcomes for patients with BRCA-mutated cancers, and several PRMT5 inhibitors targeting MTAP?deleted tumors are in late?stage clinical development. As the map of genetic dependencies continues to expand, Li sees synthetic lethality poised for much broader application across oncology.

While synthetic lethality is conceptually attractive for cancer therapy, Li stated that challenges remain to hinder its clinical success: “One major challenge is that synthetic-lethal interactions are often highly context dependent. While large?scale screens generate numbers of candidates, truly reproducible, robust, and clinically relevant synthetic?lethal pairs appear to be rare.”

He also highlighted a potential path for advancing synthetic lethality-based therapies:“One promising future direction may be the integration of network biology with machine learning, to improve hit prioritization and increase the likelihood of identifying robust, translatable synthetic?lethal targets.”

Synthetic lethality outlook:

• Synthetic lethality is expanding beyond PARP inhibitors toward broader oncology applications.

• Context-dependent biology remains a key barrier to identifying clinically robust synthetic lethal targets.

• Network biology and machine learning may improve target prioritization and translational success.

Decoding the tumor microenvironment

As tumor microenvironment biology evolves, where is mechanistic clarity beginning to translate into actionable therapies, and which signals may hold translational potential?

The biological complexity of the tumor microenvironment renders it both a scientifically fertile area in oncology and a highly challenging one for drug development. Still, Li emphasized that many insights are beginning to translate into actionable therapeutics. For example, depletion of fibroblast activation protein-positive cancer-associated fibroblasts (FAP+ CAFs) can disrupt the desmoplastic matrix, rendering tumors more susceptible to subsequent mesothelin?targeted CAR T cells and anti?PD?1 therapy.

In parallel, advances in high?resolution digital pathology, spatial transcriptomics, and machine learning are providing an increasingly detailed view for the immune landscapes of “hot” and “cold” tumors. According to Li, signals emerging from these advances hold promising translational potential:“Multiple agents targeting Tregs, MDSCs, TAMs, and TAFs are in clinical development, and combinatorial strategies capable of simultaneously modulating multiple immunosuppressive pathways within the tumor microenvironment could be a promising route to overcome immune escape.”

Tumor microenvironment breakthroughs:

• Tumor microenvironment research is turning complex biology into more actionable therapeutic strategies.

• Advanced profiling tools are uncovering immune patterns linked to treatment response and resistance.

• Agents targeting distinct tumor microenvironment components are advancing clinically, with combination strategies offering a potential route to overcome immune escape.

Biomarkers: Shifting from static to dynamic

How important has early biomarker integration become in modern oncology development, and which emerging innovations may continue transforming cancer care?

Early biomarkers, especially patient selection biomarkers, have always been an integral part of modern precision oncology. Given the high degree of tumor heterogeneity, clinically meaningful response rates are often difficult to achieve without biomarker-driven patient stratification.

Li noted a significant trend in biomarkers: the rapid expansion of cancer minimal residual disease (MRD) detection into solid tumors.With current technologies and rigorous clinical validation, circulating tumor DNA (ctDNA)?based MRD detection enables longitudinal monitoring of therapy response across the entire stages of cancer care.

More broadly, Li highlighted a key transition underway: biomarker strategies are shifting from static, prognostic markers toward dynamic, longitudinal monitoring of biological signals that are both predictive and actionable.

Biomarker transformation trends:

• Early biomarker integration is essential for patient selection in precision oncology development.

• ctDNA-based MRD testing is expanding into solid tumors and enabling longitudinal disease monitoring.

• Biomarker strategies are evolving from static risk markers toward dynamic, actionable biological signals.

Bridging scientific depth and discovery speed

Can you explain how WuXi AppTec preserves deep biological insight while still advancing programs at the speed modern oncology demands?

In oncology drug discovery, speed is essential as therapies are often complex and patient needs are urgent. Speed, however, does not come at the expense of scientific rigor. As Li explained,“Preserving scientific depth while moving at market pace is not viewed as a trade-off. Both are essential expectations that must be achieved simultaneously.”

According to Li,multi-dimensional capabilities are required for achieving that balance: capabilities grounded in causal biology;continuous anticipation of emerging scientific and market trends; and sustained investment in new drug resistance models for novel therapeutics and drug response systems tailored to emerging modes of action. These capabilities reflect the broader set of integrated capabilities that WuXi AppTec has built to enable innovators in accelerating the discovery of oncology therapies.

Looking ahead, Li noted that with the recent wave of new modalities and modes of action, the ability to translate biology into clinically meaningful outcomes is becoming stronger than ever. “Daraxonrasib is the leading development candidate for a novel class of non-covalent inhibitor that targets the active ‘ON’ conformations of mutant and wild-type KRAS, HRAS, and NRAS. The recent release of pivotal Phase 3 RASolute 302 trial results for previously treated metastatic pancreatic cancer demonstrated a median OS of 13.2 months versus 6.7 months for chemotherapy. This is a major, paradigm-shifting advance in oncology,” Li added.

These advances are transforming decades of clinical practice in oncology, pointing to a future in which therapies can be brought to patients across a broader range of cancers.

▲Representative workflow and assay toolkit used for KRAS target characterization, mechanism-of-action studies, and efficacy evaluation

Innovation execution essentials:

• Modern oncology discovery requires both scientific rigor and rapid execution.

• Integrated biological, translational, and trend-sensing capabilities help accelerate programs without compromising mechanistic depth.

• Advances in new modalities and mechanisms are strengthening the translation of biology into patient impact.

Oncology innovation is entering a new phase in which emerging modalities, deeper cancer biology, and advanced translational tools are converging to reshape therapeutic discoveries. From molecular glues and ADCs to synthetic lethality, tumor microenvironment modulation, and dynamic biomarker strategies, progress increasingly depends on integrating mechanistic insight with scalable discovery approaches. As these scientific advances mature, the ability to connect biological understanding with rapid, rigorous execution will be critical to bringing more precise and durable therapies to patients.

Key takeaways:

• Oncology innovation is moving toward more precise, biology-driven therapeutic strategies.

• New modalities and mechanisms are expanding what can be targeted in cancer drug discovery.

• Integrating scientific depth, translational tools, and execution speed will be essential for advancing next-generation cancer therapies.

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