Mounting evidence links the phenomenon of enhanced recruitment of tumor-associated macrophages towards cancer bulks to neoplastic growth, invasion, metastasis, immune escape, matrix remodeling, and therapeutic resistance. In the context of cancer progression, naïve macrophages are polarized into M1 or M2 subtypes according to their differentiation status, gene signatures, and functional roles. While the former render proinflammatory and anticancer effects, the latter subpopulation elicits an opposite impact on pancreatic ductal adenocarcinoma. M2 macrophages have gained increasing attention as they are largely responsible for molding an immune-suppressive landscape. Through positive feedback circuits involving a paracrine manner, M2 macrophages can be amplified by and synergized with neighboring neoplastic cells, fibroblasts, endothelial cells, and non-cell autonomous constituents in the microenvironmental niche to promote an advanced disease state. This review delineates the molecular cues expanding M2 populations that subsequently convey notorious clinical outcomes. Future therapeutic regimens shall comprise protocols attempting to abolish environmental niches favoring M2 polarization; weaken cancer growth typically assisted by M2; promote the recruitment of tumoricidal CD8⁺ T lymphocytes and dendritic cells; and boost susceptibility towards gemcitabine as well as other chemotherapeutic agents.

Breast cancer is the most common malignancy among females in western countries, where women have an overall lifetime risk of >10% for developing invasive breast carcinomas. It is not a single disease but is composed of distinct subtypes associated with different clinical outcomes and is highly heterogeneous in both the molecular and clinical aspects. Although tumor initiation is largely driven by acquired genetic alterations, recent data suggest microenvironment-mediated immune evasion may play an important role in neoplastic progression. Beyond surgical resection, radiation, and chemotherapy, additional therapeutic options include hormonal deactivation, targeted-signaling pathway treatment, DNA repair inhibition, and aberrant epigenetic reversion. Yet, the fatality rate of metastatic breast cancer remains unacceptably high, largely due to treatment resistance and metastases to brain, lung, or bone marrow where tumor bed penetration of therapeutic agents is limited. Recent studies indicate the development of immune-oncological therapy could potentially eradicate this devastating malignancy. Evidence suggests tumors express immunogenic neoantigens but the immunity towards these antigens is frequently muted. Established tumors exhibit immunological tolerance. This tolerance reflects a process of immune suppression elicited by the tumor, and it represents a critical obstacle towards successful antitumor immunotherapy. In general, immune evasive mechanisms adapted by breast cancer encompasses down-regulation of antigen presentations or recognition, lack of immune effector cells, obstruction of anti-tumor immune cell maturation, accumulation of immunosuppressive cells, production of inhibitory cytokines, chemokines or ligands/receptors, and up-regulation of immune checkpoint modulators. Together with altered metabolism and hypoxic conditions, they constitute a permissive tumor microenvironment. This article intends to discern representative incidents and to provide potential innovative therapeutic regimens to reinstate tumoricidal immunity.

Increasing evidence points to the role of endogenous retroviruses (ERVs) in driving cancer cell proliferation. The purpose of this study was to explore the possibility of repurposing antiretroviral agents to inhibit ERVs as a new approach to cancer treatment. We found that an integrase strand-transfer inhibitor, dolutegravir (DTG), effectively inhibited the proliferation of multiple cancer cell lines and its antiproliferative potency was positively correlated with the expression levels of the human endogenous retrovirus type K (HERV-K). DTG inhibited the expression of HERV-K in multiple human cancer cell lines and the mouse mammary tumor virus (MMTV) in the murine 4T1 mammary cancer cell line. We chose the fast-growing BT-20 cell line as a model to study the in vitro antiproliferative mechanisms of DTG. BT-20 cells overexpressing both HERV-K env and pol genes became more resistant to DTG than cells transduced with vector alone. Knockdown of HERV-K also increased DTG resistance of BT-20 cells. The antiproliferative effect of DTG correlated with enhanced expression of E-cadherin and reduction in cell motility and invasiveness. Surprisingly, DTG stimulated expression of the env gene of MMTV in vivo and promoted metastasis of 4T1 tumor cells to the lungs. Taken together, our data support the role of ERVs in tumor development and encourage the further search for antiretroviral agents to treat malignancies in which ERVs are active.

The evolution of severe acute respiratory syndrome coronavirus 2 (SARS‑CoV‑2) has followed similar trends as other RNA viruses, such as human immunodeficiency virus type 1 and the influenza A virus. Rapid initial diversification was followed by strong competition and a rapid succession of dominant variants. Host-initiated RNA editing has been the primary mechanism for introducing mutations. A significant number of mutations detrimental to viral replication have been quickly purged. Fixed mutations are mostly diversifying mutations selected for host adaptation and immune evasion, with the latter accounting for the majority of the mutations. However, immune evasion often comes at the cost of functionality, and thus, optimal functionality is still far from being accomplished. Instead, selection for antibody-escaping variants and accumulation of near-neutral mutations have led to suboptimal codon usage and reduced replicative capacity, as demonstrated in non-respiratory cell lines. Beneficial adaptation of the virus includes reduced infectivity in lung tissues and increased tropism for the upper airway, resulting in shorter incubation periods, milder diseases, and more efficient transmission between people.

The ultimate measure of viral fitness is the ability to maintain high prevalence within its host species. Effective transmission, efficient replication, and rapid immune evasion all contribute to this outcome. Over the past five years, SARS-CoV-2 has successfully adapted to humans, establishing long-term reservoirs and enabling sustained coexistence with the human population. We have observed innovative, synergistic mutations in the spike (S) protein that enhance receptor binding. Adaptation to the upper respiratory tract has shortened the incubation period, thereby facilitating viral spread. These improvements have also enabled immune escape mutations, even when such changes compromise replicative fitness. Adaptive mutations have driven intermittent selective sweeps by dominant variants. However, there are limits to functional enhancement. The receptor binding affinity of the S protein appears to have peaked between 2022 and 2023. The accumulation of fixed mutations plateaued following the emergence of BA.2.86/JN.1 around late 2023 and early 2024. Purifying selection has been the dominant evolutionary force acting on nonsynonymous mutations in the Omicron lineage, and the overall fitness impact of missense mutations in key viral proteins has declined. Additionally, due to weak selection pressure on synonymous mutations, the codon adaptation index in humans has been decreasing among Omicron subvariants. As a result, Omicron lineages have replicated less efficiently in cell cultures compared to the original virus, and recent variants show further attenuation in animal models. In the human population, this attenuation is reflected in declining COVID-19-related mortality, despite persistently high infection rates.

Using a combined top‐down (i.e., operator‐directed) and bottom‐up (i.e., cell‐directed) strategy, an Under‐oil Open Microfluidic System (UOMS)‐based microtumor model is presented for investigating tumor cell migration and anti‐metastasis drug test. Compared to the mainstream closed microfluidics‐based microtumor models, the UOMS microtumor model features: i) micrometer‐scale lateral resolution of surface patterning with open microfluidic design for flexible spatiotemporal sample manipulation (i.e., top‐down); ii) self‐organized extracellular matrix (ECM) structures and tumor cell‐ECM spontaneous remodeling (i.e., bottom‐up); and iii) free physical access to the samples on a device with minimized system disturbance. The UOMS microtumor model – allowing a controlled but also self‐organized, cell‐directed tumor‐ECM microenvironment in an open microfluidic configuration – is used to test an anti‐metastasis drug (incyclinide, aka CMT‐3) with a triple‐negative breast cancer cell line (MDA‐MB‐231). The in vitro results show a suppression of tumor cell migration and ECM remodeling echoing the in vivo mice metastasis results.