Drug development in oncology is increasingly moving towards integrated strategies that consider tumour cells, their microenvironment and anatomical context
The oncology drug development landscape continues to expand at pace. Increasingly, progress is driven not only by the identification of new molecular targets, but also by advances in how these targets are engaged. Therapeutic strategies now extend beyond tumour cells to the broader tumour microenvironment (TME), and in approaches that may be applicable across tumour types.
Recent analyses of oncology pipelines suggest that many late-stage research programmes continue to focus on (few, selected) well-established targets, whereas earlier development is characterised by diversification in therapeutic platforms (Nat Rev Drug Discov. 2025 Dec 17). So where will the next meaningful advances in patient outcomes arise – from discovering novel biology, or from more effective ways of exploiting existing biology?
One area of active interest is the development of immune-stimulating antibody conjugates (ISACs). These agents combine tumour-directed antibodies (e.g. targeting HER2, PD-L1, etc.) with payloads designed to activate both innate and adaptive immunity, including TLR7, TLR8, TLR9 or STING agonists. Preclinical studies demonstrate the potential to enhance antigen presentation, increase immune-cell infiltration, and promote immunological memory (Nat Rev Clin Oncol. 2024 Mar;21(3):203-223). Early-phase clinical trials are ongoing, and it remains to be determined how these agents will compare with, or complement, established antibody-drug conjugates (ADCs) with cytotoxic payloads.
Another TME-directed strategy is targeting fibroblast activation protein (FAP). FAP represents an attractive pan-tumour target as it is expressed in cancer-associated fibroblasts across multiple tumour types, while showing minimal expression in normal adult tissues (Cancer Metastasis Rev. 2020 Sep;39(3):783–803). A range of therapeutic approaches are under development, including FAP-radioligands, FAP-ADCs and FAP-small-molecule conjugates. This breadth of approaches reflects growing interest in stromal targets, although their clinical impact and therapeutic window remain to be fully defined.
For TME-directed approaches, careful evaluation of on-target, off-tumour effects will be essential. At the ESMO Targeted Anticancer Therapies (TAT) Congress 2026, the ongoing challenges and approaches in drug delivery to the central nervous system were discussed during an educational session on new drugs for new targets. Indeed, advances in kinase inhibitor design have improved blood-brain barrier penetration, contributing to better control of intracranial disease (Clin Cancer Res. 2021 Jan 1;27(1):189-201). However, greater CNS exposure has also been associated with a range of neurological adverse events, including cognitive and behavioural effects, underscoring the need for careful toxicity characterisation (Ann Oncol. 2020 Sep;31(9):1109-1111).
Collectively, these developments reflect a broader framework in drug development in oncology moving from tumour-centric targeting towards integrated strategies that consider tumour cells, their microenvironment and anatomical context. The expanding range of novel targets and therapeutic platforms also prompts important questions – How should emerging approaches be prioritised? What level of preclinical evidence is sufficient to support early clinical translation? And how can innovation be balanced with safety as therapeutic approaches become more complex?
Ultimately, the challenge will be to translate this expanding biological and technological complexity into treatments that deliver meaningful, durable benefit for patients.
