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Two recent genomic studies suggest that a large fraction of human tumors evolves in the presence of limited negative selection against somatic mutations. In this context, specific genetic defects enable the establishment of a hypermutant state that may constitute a target for immunotherapeutic interventions. [ABSTRACT FROM AUTHOR]

Two resource articles recently published in Cell demonstrate that the elevated phenotypic complexity of the immune infiltrate in human lung adenocarcinomas and renal cell carcinomas can be reliably dissected with mass cytometry. These findings may pave the way to a new era of precision cancer immunotherapy. [ABSTRACT FROM AUTHOR]

At odds with conventional chemotherapeutics, targeted anticancer agents are designed to inhibit precise molecular alterations that support oncogenesis or tumor progression. Despite such an elevated degree of molecular specificity, many clinically employed and experimental targeted anticancer agents also mediate immunostimulatory or immunosuppressive effects that (at least in some settings) influence therapeutic efficacy. Here, we discuss the main immunomodulatory effects of targeted anticancer agents and explore potential avenues to harness them in support of superior clinical efficacy. [ABSTRACT FROM AUTHOR]

Evolving neoplasms accumulate non-synonymous mutations at a high rate, potentially enabling the expression of antigenic epitopes that can be recognized by the immune system. Since they are not covered by central tolerance, such tumor neoantigens (TNAs) should be under robust immune control as they surge. However, genetic defects that impair cancer cell eradication by the immune system coupled with the establishment of local immunosuppression can enable TNA accumulation, which is generally associated with improved clinical sensitivity to various immunotherapies. Here, we explore how tumor-intrinsic factors and immunological processes shape the mutational and antigenic landscape of evolving neoplasms to influence clinical responses to immunotherapy, and propose strategies to achieve robust immunological control of the disease despite disabled immunosurveillance. Highlights The recognition of TNAs by the host immune system has a key role in natural immunosurveillance and dictates the outcome of most (if not all) current cancer (immuno)therapies. A panel of tumor-intrinsic and microenvironmental factors influence TNA evolution over space and time, partially explaining the heterogeneity of clinical responses to (immuno)therapies. The tumor and its host coevolve in a highly dynamic manner, which shapes the mechanisms whereby progressing neoplasms evade immune recognition as they become resistant to (immuno)therapy. Unveiling the trajectories of TNA evolution may help define quantitative, qualitative, and temporal aspects of the anticancer immune response that can assist clinical decision-making. [ABSTRACT FROM AUTHOR]

The metastatic spread of malignant cells to distant anatomical locations is a prominent cause of cancer-related death. Metastasis is governed by cancer-cell-intrinsic mechanisms that enable neoplastic cells to invade the local microenvironment, reach the circulation, and colonize distant sites, including the so-called epithelial-to-mesenchymal transition. Moreover, metastasis is regulated by microenvironmental and systemic processes, such as immunosurveillance. Here, we outline the cancer-cell-intrinsic and -extrinsic factors that regulate metastasis, discuss the key role of natural killer (NK) cells in the control of metastatic dissemination, and present potential therapeutic approaches to prevent or target metastatic disease by harnessing NK cells. [ABSTRACT FROM AUTHOR]