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An NNMT inhibitor reduces tumour burden and metastasis in multiple mouse cancer models and restores immune checkpoint blockade efficacy by decreasing cancer-associated-fibroblast-mediated recruitment of myeloid-derived suppressor cells and reinvigorating CD8⁺ T cell activation.

Radiotherapy induces expression of the EGFR ligand amphiregulin, which promotes metastasis growth at remote sites in mouse models and human patients by shifting myeloid cells towards an immunosuppressive state.

Since the publication of the first issue of Nature Reviews Clinical Oncology, we have witnessed advances in multiple research areas that have culminated in improved outcomes for many cancer types, although substantial unmet needs remain for a majority of patients worldwide. Here, we have asked experts in several key specialities to reflect on the progress from the past 20 years and propose the next steps to enable further advances. Although we are aware that this Viewpoint cannot provide full coverage of the vast field that is clinical oncology, we hope that these messages inspire a diverse range of readers.

Activation of the stimulator of interferon genes (STING) can induce immunity in various cancer therapies, but delivery of STING agonists to tumours is challenging. Now a metal-based polymeric nanoparticle delivers STING agonists to tumours upon disruption of endothelial cells in tumour vasculature and targets tumour-associated macrophages, eliciting anti-tumour immune response in hard-to-treat cancer models.

Reanalysis of the immunotherapy-treated MSK-IMPACT cohort finds that chromosomal arm-level aneuploidy scores are an independent predictor of survival for patients with low tumor mutational burden.

Aneuploidy, a defining feature of cancer, is linked to immune evasion and therapeutic resistance. This Perspective reviews approaches to quantify tumor aneuploidy and evaluates its potential as a biomarker for guiding immune checkpoint blockade.

The interaction between radiotherapy and the host immune system has uncovered new mechanisms that can be exploited to improve the efficacy of radiotherapy. In this article, the authors highlight data providing new explanations for the success or failure of radiotherapy, and postulate, using radiation-induced tumour equilibrium (RITE) as an example, how the combination of immune-modulation and radiation could tip the balance of the host immune response to promote cure.

Diagnostic improvements and earlier detection of tumors have resulted in the emergence of a shift from Halsted paradigm, which has encouraged the use of systemic adjuvant therapy. With these changes in tumor paradigm, the rationale for local treatment as a curative treatment strategy has been challenged. This Viewpoint emphasizes the importance of local control in this scenario.

Even after complete resection of nonmetastatic pancreatic cancer, recurrence rates are high. Combined modality therapy including radiation therapy reduces the recurrence rate and improves disease-free survival for several types of tumor of the gastrointestinal tract, but the use of adjuvant radiotherapy for pancreatic cancer is controversial. In this Review, the authors discuss the studies—prospective and retrospective—and the issues surrounding the use of adjuvant radiotherapy for pancreatic cancer.

Spurr et al. identify high pretreatment aneuploidy score as a potential biomarker in patients with NSCLC who benefit from concurrent radiation and immune checkpoint inhibition, in immunogenomic analysis of data from a phase I clinical trial.

A nanoscale metal–organic framework that modulates the immunological and mechanical properties of the tumour microenvironment enhances the outcomes of radiotherapy–radiodynamic therapy, especially when combined with checkpoint blockade.

The emergence of tumour adaptive radioresistance can limit the success of radiation therapy and immunotherapy in breast cancer. In this study, the authors demonstrate that CD47 and HER2 are coordinating in tumor response to radiation and that co-blockage of both receptors can eliminate radiorestistant breast cancer cells.

A recent study challenges the view that radiation-induced apoptosis is beneficial in tumor therapy by showing that caspase 3–mediated apoptosis in response to ionizing radiation activates a growth signaling cascade in tumor cells, thereby stimulating tumor repopulation (pages 860–866). These results may have important implications for the clinical use of radiotherapy or chemotherapy to induce apoptosis in tumors.

Lymphocytes are considered one of the most radiosensitive cell types in the body. Here the authors show that unlike circulating lymphocytes, tumor-infiltrating T cells survive therapeutic doses of irradiation, remaining functional and contributing to radiotherapy induced anti-tumor immunity.

Sepsis due to multidrug resistant pathogens is the most common cause of death in intensive care units. Here, the authors report that fecal microbiota transplant (FMT) can rescue mice from lethal sepsis of pathogens isolated from stool of a critically ill patient and show that FMT reverses the immunosuppressive effect induced by the pathogen community.

This Perspectives article expands on the previously proposed clinical state of metastasis termed 'oligometastases' that refers to restricted tumor metastatic capacity. The authors outline the concept, discuss the evidence and the treatment implications and go on to describe ongoing studies in the field.

RAD51 has been implicated in replication fork processing and restart in response to replication stress. Here, authors reveal mechanistic aspects of non-enzymatic roles of RAD51 for fork reversal and cooperation with FBH1.

Nanoparticles can stimulate tumour microenvironment to promote anti-tumour immunity. Here, the authors show that the combination of delivering drugs by a nanoscale coordination polymer and anti-PD-L1 is synergistic in treating murine colorectal cancer.

Blockade of PD-L1 is usually not very effective in colon cancer patients. Here, the authors show the efficacy of PD-L1 blockade in combination with coordination polymer nanoparticles carrying oxaliplatin and a photosensitizer to induce anti-tumor immunity in metastatic models of colon cancer.

The oligometastasis hypothesis suggests certain metastases are limited in extent and curable with focal therapies. Here they identify three integrated molecular subtypes of colorectal cancer liver metastasis, which complement clinical risk stratification to distinguish the subset of oligometastatic patients.

p50 is a constitutively produced NF-κB subunit that modulates the response to DNA damage. Here, the authors show that activation of ATR during S phase induces p50 interaction with BARD1 resulting in p50 mono-ubiquitination, facilitating cell cycle progression and promoting chromosome integrity.

Tumors often develop resistance to radiotherapy. Here the authors show that irradiation leads to a CCR2-dependent infiltration by myeloid derived suppressor cells that promote radio-resistance through inhibition of adaptive immune responses and that the use of CCR2 antibodies in mice reduces such resistance.

Radiotherapy is known to have local immunomodulatory effects, while an effective systemic immune response is an issue. Here, the authors report on nMOF radiosensitizers for enhanced radiotherapy which in combination with anti-PD-L1 antibodies result in a systemic immune response to distant tumors.

Combining immune checkpoint inhibition with radiotherapy–radiodynamic therapy, enabled by intratumorally injected nanoscale metal–organic frameworks, promotes systemic antitumour immunity and tumour rejection in mouse models of breast and colorectal cancer.

The prognosis for locally advanced pancreatic carcinoma remains dismal despite advances in chemotherapy and radiotherapy over the past few decades. The use of radiotherapy for pancreatic carcinoma is often disputed because of the hypothesis that patients with pancreatic cancer die from distant metastases. This Review discusses the data from prospective and retrospective studies evaluating radiotherapy and other treatment options for locally advanced pancreatic carcinoma.

The m⁶A reader protein YTHDF1 suppresses the clearance of tumour cells by enhancing the translation of lysosomal proteases in dendritic cells and thereby suppressing tumour antigen presentation.

Combining radiation and immune checkpoint blockade is a promising treatment strategy, yet the mechanisms and optimal dosing strategies are not well known. A new study finds that a specific radiation dose can activate secretory club cells to promote the anti-tumor effects of radiotherapy combined with immunotherapy in NSCLC.

The oligometastatic state is generally considered to constitute an intermediate point along the spectrum of cancer dissemination at which the metastatic burden is limited and local ablative therapies can result in meaningful clinical benefit, and possibly even cure. In this Review, Katipally et al. reframe the oligometastatic phenotype as a dynamic state that expands beyond merely the number or size of metastases. They highlight important risk factors defining the metastatic spectrum that can inform both staging and therapy, and identify themes in the literature that might guide strategies to optimally combine metastasis-directed local therapies with modern systemic treatments.