The Shift to Complex Modalities for Cancer Treatment

A wide range of advanced therapies for various oncology indications are under development today, including next-generation antibody-based therapies, genetically engineered cell therapies, RNA-based medicines, radioligand therapies, personalized cancer vaccines, and immunotherapies addressing novel biomarkers, among others.1-4 Many of these therapies leverage novel delivery systems to achieve more targeted solutions and address multiple targets simultaneously for increased efficacy.

To learn more about the new targets and modalities being developed to improve cancer treatment, PharmTech spoke with Tim Heffernan,PhD,vice president and head of the Therapeutics Discovery Division at The University of Texas MD Anderson Cancer Center. Heffernan shared his thoughts on new approaches to fighting solid and liquid tumors, challenges developers face when translating emerging technologies from research into the clinic and commercialization, and a few promising preclinical and clinical candidates.

What newly identified targets are eliciting the greatest interest?

Heffernan: There has been a clear shift toward more complex, precision-driven strategies that exploit oncology targets through multiple complementary therapeutic approaches.

Tumor-specific antigens are increasingly leveraged as molecular “beacons” to anchor therapies that deliver cytotoxic payloads, such as antibody-drug conjugates (ADCs); redirect or amplify antitumor immunity via immune cell engagers or engineered cellular therapies (eg, chimeric antigen receptor [CAR]-T and CAR-NK [natural killer] cells); and localize high-energy, short-range radiation through radioligand therapies (RLTs).

As pharmaceutical R&D capabilities have advanced, the portfolio of high-priority tumor-selective targets has expanded beyond established antigens such as CD19, human epidermal growth factor receptor 2 (HER2), and trophoblast cell surface antigen 2 (TROP2) to include B-cell maturation antigen (BCMA), B7-H3, delta-like protein 3, prostate-specific membrane antigen (PSMA), 6 transmembrane epithelial antigen of the prostate 1 (STEAP1), and others. The growing diversity of targets in development underscores major advances in protein engineering and tumor-targeting technologies.

In parallel, a deeper understanding of protein structure and conformational dynamics has enabled small-molecule discovery to move beyond traditional catalytic inhibition toward allosteric, covalent, and induced proximity-based mechanisms of action. These innovations have fundamentally reshaped strategies for targeting tumor dependencies and have provided a blueprint for pharmacologically addressing historically “undruggable” targets, including Kirsten rat sarcoma virus oncogene homologue (KRAS), p53, and β-catenin.

Which new solutions are overcoming challenges presented by the tumor microenvironment?

Heffernan: Advances in protein engineering are creating new opportunities to enhance spatial control and tumor selectivity while incorporating mechanisms to counter the immunosuppressive tumor microenvironment. Key areas of innovation include:

• Immune cell engagers(eg, CD3-, 4-1BB-, and CD16a-based formats) that localize immune activation within tumors, increasing antitumor potency while minimizing systemic toxicity.
• Bispecific and multispecific antibodies armored with or without costimulatory signaling (eg, CD28) that combine tumor targeting, immune cell engagement, and T-cell activation within a single construct, enabling deeper and more durable immune responses. Most notable is the development of advanced programmed death-ligand 1 [PD-L1] x vascular endothelial growth factor (VEGF) bispecific antibodies.
• Engineered cytokines and targeted delivery strategies (eg, interleukin [IL]-12–based approaches) designed to harness potent immunostimulatory activity while mitigating dose-limiting systemic toxicities through improved localization and control.

Are there any notable advances/step changes in treatment approaches for liquid tumors?

Heffernan: Several notable advances have reshaped treatment paradigms in liquid tumors. One major area of progress involves strategies to redirect the immune system. T-cell engager (TCE) antibodies have generated significant interest due to their ability to complement CAR-T cell therapy. In B-cell lymphomas, CD20 × CD3 bispecific antibodies have emerged as effective therapies, with multiple TCEs now approved. Similarly, BCMA × CD3 and G-protein-coupled receptor 5D (GPRC5D) × CD3 TCEs have been approved for the treatment of multiple myeloma.

Another important advance is the targeting of molecular subtypes in leukemia. Most notably, menin inhibitors have been approved for acute myeloid leukemia and acute lymphoblastic leukemia (ALL). Revumenib and ziftomenib inhibit the interaction between menin and mixed lineage leukemia (MLL) fusion proteins, exploiting a key epigenetic dependency required for leukemogenesis. These agents represent precision therapies specifically designed for leukemias harboring MLL rearrangements or nucleophosmin 1 mutations.

Finally, progress has been made in addressing drug resistance. Acquired resistance has limited the durability of covalent Bruton tyrosine kinase (BTK) inhibitors in chronic lymphocytic leukemia (CLL). The approval of pirtobrutinib, a noncovalent BTK inhibitor, for patients with relapsed or refractory CLL provides an additional therapeutic option and helps overcome resistance to earlier-generation agents.

What other areas of cancer therapy R&D are generating real excitement?

Heffernan: We have witnessed a dramatic acceleration in pharmaceutical R&D, with several therapeutic modalities emerging as major drivers of innovation and investment across biopharma.

ADCs continue to dominate the landscape, demonstrating dramatic clinical efficacy and the potential to replace traditional chemotherapy by delivering highly tumor-selective cytotoxicity. The field is supported by both scale, whereby there are approximately 2170 active ADC assets currently under investigation, as well as strong regulatory momentum. Next-generation ADCs incorporating novel payloads, dual-payload designs, and bispecific antigen engagement are rapidly advancing into the clinic.

Biologic therapies have become a high-priority area due to their modular architecture and the maturation of protein engineering technologies, which together enable exploration of previously inaccessible target spaces. This includes bispecific antibodies and immune cell engagers, developed with or without costimulatory functionality, to achieve more precise and potent immune activation.

RLTs are emerging as the next major wave of targeted cytotoxic delivery, with next-generation programs focused on alpha-emitting radionuclides. Recent advances are expected to expand the field beyond PSMA-based targeting and into a broader range of disease indications.

Cellular therapies have demonstrated transformative efficacy in hematologic malignancies but remain constrained by manufacturing complexity and cost. Despite these challenges, the field continues to attract substantial investment as innovation shifts toward in vivo engineering and more scalable delivery paradigms.

Induced proximity–based therapeutics represent a rapidly evolving area, encompassing technologies designed to modify, degrade, redirect, or sequester disease-relevant proteins. Beyond molecular glues, recent advances such as regulated induced proximity–targeting chimeras have generated significant excitement, supported by encouraging early clinical data.

Finally, artificial intelligence and machine learning are reshaping oncology R&D by enabling more informed target selection, optimized molecular design, and increasingly efficient development cycles. Enthusiasm is growing as AI-designed oncology drugs have now entered clinical testing.

Are there any truly new modalities in development for cancer treatment that are creating waves?

Heffernan: The industry’s shift toward increasingly complex, precision-driven modalities has become evident. Next-generation ADCs incorporating improved linker chemistries, novel payloads, and more refined targeting strategies are positioned to further enhance both efficacy and tolerability. Multispecific immune engagers with integrated costimulatory functions are redefining the depth and durability of antitumor immune responses, enabling more controlled and potent immune activation.

Radioligand therapies represent a distinct and rapidly expanding modality that uniquely integrates molecular targeting with localized radiotherapy, offering a new paradigm for tumor-selective cytotoxicity. Targeting KRAS has fundamentally redefined the concept of “druggable” oncology targets. With 2 KRAS inhibitors now approved, next-generation approaches, including pan-RAS and more selective mutant-specific inhibitors, are demonstrating dramatic clinical responses across multiple tumor types.

Collectively, these advances align with 2025 deal-making trends, in which biologics and advanced therapeutic platforms dominated transaction activity, reflecting strong investor confidence in scalable, next-generation oncology technologies.

Can you point to any specific preclinical or clinical candidates with real promise?

Heffernan: Beyond individual assets, several broader concepts are emerging as areas of significant interest. PD-L1 × VEGF bispecific antibodies represent one such area, with multiple programs advancing in the clinic and ivonescimab data serving as a key benchmark for the field.

Targeting KRAS has also seen meaningful progress. Two mutant-selective KRAS inhibitors are now approved, and a broader portfolio of KRAS-targeting agents is advancing through clinical development. In particular, clinical activity observed with RMC-6236 (daraxonrasib) in pancreatic ductal adenocarcinoma has generated substantial interest.

ADCs continue to evolve rapidly. Building on the success of HER2- and TROP2-targeting ADCs, the field has expanded to include programs directed against targets such as B7-H3, claudin 18.2 (CLDN18.2), and Nectin-4. Additional innovation has focused on the development of bispecific ADCs that engage 2 independent antigens or epitopes, as well as on diversification of payloads beyond traditional topoisomerase inhibitors, which is an area attracting particularly strong interest.

In vivo engineering of cell therapies has also gained momentum, driven by substantial investment in approaches aimed at eliminating complex ex vivo manufacturing and improving scalability. These strategies typically involve delivery of genetic payloads to specific immune cell populations via lipid nanoparticles or viral vectors to induce CAR expression and enhance activity and persistence. As these programs progress clinically, this area is expected to remain a major focus for the field.

Finally, AI is increasingly influencing drug discovery and development. Investments in companies, such as Insilico, Isomorphic, Recursion, and Generate Biomedicines, highlight growing confidence in AI-informed drug design. As AI-designed therapeutics enter the clinic, the field will gain greater insight into their true impact on discovery timelines, efficiency, and overall productivity.

What do you see as the biggest challenges to translating these new modalities into effective, approved therapies for cancer treatment?

Heffernan: Despite unprecedented advances in cancer biology and therapeutic innovation, translating oncology targets and modalities into effective, approved therapies remains exceptionally challenging. The biggest hurdles remain the biological complexity of tumors, limited therapeutic index, and toxicity.

A central challenge is the biological complexity of cancer. Tumors are genetically heterogeneous, dynamically evolving systems embedded within suppressive microenvironments. Targets that appear compelling in preclinical models often prove context-dependent in patients, where pathway redundancy, clonal diversity, and adaptive resistance limit efficacy. However, recent technological advances in spatial biology and single-cell sequencing have advanced our understanding of tumor heterogeneity, tumor evolution, and mechanisms of acquired resistance. These data have informed new strategies to enhance efficacy and durability through rational drug combinations.

Although toxicity profiles are modality-specific, toxicity remains a major challenge in oncology drug development. Toxicity is primarily driven by the normal physiological function of a drug target, imperfect selectivity of the therapeutic, heterogeneous antigen expression, or systemic immune activation induced by on-target, off-tumor engagement. These liabilities often narrow the therapeutic index, limit dose intensity or treatment duration, and complicate the development of rational combination regimens required to achieve durable clinical responses.

What projects is MD Anderson working on?

Heffernan: Our organization is advancing a growing portfolio of therapeutic programs that span multiple modalities, including small molecules, radiopharmaceuticals, and advanced protein-based therapeutics. What makes this work distinctive is the way discovery science, translational research, and clinical development operate as a single, integrated R&D engine. With all functions under one roof, we can use emerging clinical data to guide portfolio decisions in real time and rapidly translate new scientific concepts into clinical testing. This model allows us to progress a range of innovative assets efficiently and with a clear line of sight from early biology to patient impact.

References

1. Miao H, Fang Y, Pan C, etal. Transforming the landscape of cancer treatment with seven promising novel therapies: evolution and future perspectives. Med. Plus. 2025;2(2): 100087. doi: 10.1016/j.medp.2025.100087
2. Gores M, Lutznayer S. Breaking new ground: advancing cancer care with novel therapeutic modalities. IQVIA white paper, 2024. https://www.iqvia.com/-/media/iqvia/pdfs/library/white-papers/breaking-new-ground-advancing-cancer-care-with-novel-therapeutic-modalities.pdf
3. Rosenberg J. Revolutionary therapeutic modalities transforming cancer care. Linical. December 16, 2025. https://www.linical.com/articles-research/revolutionary-therapeutic-modalities-transforming-cancer-care
4. Meade E, Garvey M. Comparison of current immunotherapy approaches and novel anti-cancer vaccine modalities for clinical application. Int. J. Mol. Sci. 2025;26(17), 8307; doi:10.3390/ijms26178307

About the author

Cynthia A. Challener, PhD, is a contributing editor to PharmTech.