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FGFR inhibitors are now approved for use in patients with advanced-stage urothelial carcinoma, cholangiocarcinoma and myeloid or lymphoid neoplasms that harbour certain FGFR alterations. Nonetheless, challenges such as tolerability and acquired resistance limit the clinical potential of these agents. In this Review, the authors summarize the available clinical data on FGFR inhibitors, describe promising novel agents and highlight future research directions that might optimize the efficacy of FGFR-targeted therapies.

Patients with early stage hepatocellular carcinoma typically undergo resection, liver transplantation or local ablation; however, 30–50% will have disease recurrence at 3 years. The authors of this Review describe the tumour immune microenvironment and mechanism of action of immunotherapies, and discuss the available evidence from phase II/III trials of neoadjuvant and adjuvant treatment approaches in this setting.

Increasing evidence indicates that signalling networks activated downstream of oncogenic alterations contribute fundamentally to cancer immune evasion, including by promoting the accumulation of regulatory T (T_reg) cells and other immunosuppressive cells in the tumour microenvironment (TME). Herein, the authors discuss the mechanisms via which cancers engage T_reg cells to evade antitumour immunity, as well as the characteristics of T_reg cells in the TME and their roles in resistance to immune-checkpoint inhibitors. Considering these aspects, they propose the concept of ‘immuno-genomic cancer evolution’ for tumorigenesis and the related paradigm of ‘immuno-genomic precision medicine’, postulating that the specific characteristics of cancer, especially genetic profiles that correlate with particular immunosuppressive networks in the TME, are likely to inform individualized strategies for combining molecularly targeted agents with immunotherapies.

In 2023, the US FDA approved several new cancer drugs and biologic agents, including seven small-molecule inhibitors, four bispecific T cell engagers, two anti-PD-1 antibodies and one cell therapy product. Regulatory focus areas included analyses of biomarker-positive subgroups that drive efficacy, equipoise in randomized controlled trials and a new authority to require confirmatory trials be underway before accelerated approval.

Ataxia telangiectasia and Rad3-related protein serine/threonine kinase (ATR) is a mediator of the cellular replication stress response that, upon activation, initiates a cascade of coordinated reactions that ultimately enables DNA repair. This biological function makes ATR an attractive therapeutic target in cancers with elevated replication stress or DNA-repair deficiency. This Review discusses the currently available results from clinical trials testing ATR inhibitors as well as challenges and solutions in the development of this therapeutic class.

Dendritic cells (DCs) are antigen-presenting cells that function at the interface between innate and adaptive immunity, thereby acting as key mediators of antitumour immune responses and immunotherapy efficacy. In this Review, the authors outline the emerging complexity of intratumoural DC states that is being revealed through single-cell analyses as well as the contributions of different DC subsets to anticancer immunity and the activity of immune-checkpoint inhibitors. The authors also discuss advances in the development of DC-based cancer therapies and considerations for their potential combination with other anticancer therapies.

The US FDA Accelerated Approval of sotorasib required the sponsor to conduct a randomized trial that compared the safety and efficacy of the approved dose with a lower dose. These results, recently disclosed, have important implications for patients, payers, oncologists and the pharmaceutical industry.

Durable responses with first-line platinum-based chemotherapy for advanced-stage urothelial carcinoma are rare, and patient outcomes are poor. Recently, CheckMate 901 became the first phase III trial to establish a significant overall survival benefit from a combined chemoimmunotherapy approach in this disease setting. Herein, we discuss key findings from CheckMate 901 and their implications in the context of a rapidly evolving treatment landscape.

Various BRAF alterations are found and function as oncogenic drivers across diverse cancer types. BRAF inhibitor-based therapy has improved outcomes for patients with cancers harbouring BRAF^V600 mutations, although resistance develops in most, and the current inhibitors are not effective against other types of BRAF alterations. In this Review, the authors describe the mechanisms underlying oncogenic BRAF signalling, as well as pan-cancer and lineage-specific mechanisms of intrinsic, adaptive and acquired resistance to BRAF inhibitors. They also discuss novel RAF inhibitors and drug combinations designed to overcome these resistance mechanisms and/or expand the applicability of molecularly targeted therapy to a broader range of BRAF-mutant cancers.

Several novel personalized therapies focus on targeting neoantigens. Such strategies require the identification of suitable vaccine neoepitopes or neoantigen-specific T cell receptor (TCR) clonotypes. Herein, we discuss a recently published report that describes a combined transcriptional and phenotype signature, NeoTCR_PBL, that enables the minimally invasive identification of rare neoantigen-specific TCRs from peripheral blood that might enable more-effective T cell-based therapies against cancer.