The tumor microenvironment (TME) plays a critical role in shaping immune responses against cancer. Recent studies have highlighted the importance of dendritic cells (DCs) in the transport and presentation of tumor antigens. Ruhland et al. demonstrated that migratory DCs in tumors utilize synaptic transfer of vesicles to share antigens with resident DCs, facilitating T cell activation (ref: Balan doi.org/10.1016/j.ccell.2020.05.013/). This mechanism underscores the significance of intercellular communication in the TME. Additionally, engineered cell-membrane-coated nanoparticles have been shown to directly present tumor antigens, enhancing anticancer immunity by mobilizing specific T cell subsets (ref: Jiang doi.org/10.1002/adma.202001808/). The study of soluble NKG2D ligands, particularly sMIC, revealed that elevated levels correlate with poor responses to PD1/PDL1 blockade therapy in melanoma, indicating a potential biomarker for treatment outcomes (ref: Basher doi.org/10.1186/s13045-020-00896-0/). Furthermore, single-cell transcriptomic analyses have identified diverse B cell subtypes within the TME of non-small cell lung cancer (NSCLC), revealing a complex interplay where plasma-like B cells can inhibit tumor growth in early stages but may promote it in advanced stages (ref: Chen doi.org/10.1186/s13059-020-02064-6/). Lastly, SOD3's role in enhancing T cell infiltration into tumors by upregulating LAMA4 in endothelial cells suggests a pathway for converting immunologically 'cold' tumors into 'hot' ones, thereby improving therapeutic responses (ref: Carmona-Rodríguez doi.org/10.1136/jitc-2019-000432/).

Checkpoint inhibitors have revolutionized cancer treatment, particularly in combination therapies. The IMspire150 trial evaluated the efficacy of combining atezolizumab with BRAF and MEK inhibitors in patients with unresectable advanced BRAF-mutant melanoma. Results showed a significant improvement in progression-free survival (PFS) with atezolizumab compared to control (15.7 vs 10.6 months; HR 0.778; p=0.025), highlighting the potential of this combination therapy (ref: Gutzmer doi.org/10.1016/S0140-6736(20)30934-X/). In another study, bispecific antibodies targeting CD28 were shown to enhance the antitumor efficacy of PD-1 immunotherapy, suggesting a synergistic approach to overcoming resistance to checkpoint blockade (ref: Waite doi.org/10.1126/scitranslmed.aba2325/). A meta-regression analysis indicated that tumor mutational burden (TMB) serves as a predictive biomarker for response to immune checkpoint inhibitors, with higher TMB correlating with improved overall survival and objective response rates (ref: Osipov doi.org/10.1158/1078-0432.CCR-20-0458/). However, the relationship between TMB and treatment toxicity remains unclear, necessitating further investigation. Additionally, a phase I study of mogamulizumab in combination with durvalumab or tremelimumab demonstrated acceptable tolerability, paving the way for future combination therapies in advanced solid tumors (ref: Zamarin doi.org/10.1158/1078-0432.CCR-20-0328/).

Innovative drug delivery systems are crucial for enhancing therapeutic efficacy, particularly in targeting lymph nodes. Schudel et al. reviewed material designs that facilitate drug accumulation in lymph nodes, emphasizing the need for instructive delivery vehicles that can target specific immune cell subtypes (ref: Schudel doi.org/10.1038/s41578-019-0110-7/). Another study introduced a programmable multistage drug delivery system that overcomes lymphatic transport barriers, enabling targeted delivery to lymph node-resident cells (ref: Schudel doi.org/10.1038/s41565-020-0679-4/). Furthermore, the role of long noncoding RNA INCR1 in regulating tumor interferon signaling was highlighted, showing its impact on PD-L1 expression and T cell immunosuppression (ref: Mineo doi.org/10.1016/j.molcel.2020.05.015/). The development of multiplexed immunopeptidomics has also advanced our understanding of MHC I repertoire alterations in response to cancer therapies, providing insights into immune evasion mechanisms (ref: Stopfer doi.org/10.1038/s41467-020-16588-9/). These advancements in drug delivery systems and molecular understanding are paving the way for more effective cancer treatments.

Understanding the mechanisms of cancer immunotherapy is essential for improving treatment outcomes. A CRISPR-Cas9 screen identified p38 kinase as a critical target for enhancing the efficacy of adoptive immunotherapies, revealing key phenotypic qualities of effective anti-tumor T cells, such as cell expansion and differentiation (ref: Gurusamy doi.org/10.1016/j.ccell.2020.05.004/). Additionally, the CBASS immunity system in bacteria was found to utilize cyclic oligonucleotide signals to initiate antiviral responses, providing insights into immune sensing mechanisms that could be leveraged for cancer therapies (ref: Lowey doi.org/10.1016/j.cell.2020.05.019/). The targeting of soluble NKG2D ligands in melanoma has shown promise in reprogramming NK cell function and enhancing responses to PD1 blockade, indicating a potential therapeutic strategy for improving immunotherapy efficacy (ref: Basher doi.org/10.1186/s13045-020-00896-0/). Furthermore, engineered nanoparticles that present tumor antigens directly to immune cells have demonstrated the ability to stimulate antigen-specific T cell populations, highlighting the importance of antigen presentation in immunotherapy (ref: Jiang doi.org/10.1002/adma.202001808/). These findings underscore the complexity of immune interactions in the TME and the need for targeted strategies to enhance the effectiveness of immunotherapies.

The intersection of COVID-19 and cancer has raised significant concerns regarding patient outcomes and treatment strategies. A study on lung cancer patients revealed that COVID-19 was severe in 62% of cases, with a mortality rate of 25%, indicating a heightened risk for this population (ref: Luo doi.org/10.1016/j.annonc.2020.06.007/). Interestingly, the presence of human leukocyte antigen (HLA) supertypes did not significantly differ between mild and severe cases, suggesting that genetic factors may not solely dictate outcomes (ref: Luo doi.org/10.1016/j.annonc.2020.06.007/). In a prospective cohort study, chemotherapy within four weeks prior to COVID-19 diagnosis did not significantly affect mortality rates, challenging assumptions about the risks associated with ongoing cancer treatments during the pandemic (ref: Lee doi.org/10.1016/S0140-6736(20)31173-9/). Additionally, the use of convalescent plasma in hospitalized COVID-19 patients showed mixed results, with many receiving additional therapies, complicating the assessment of efficacy (ref: Hegerova doi.org/10.1182/blood.2020006964/). These findings highlight the need for tailored approaches in managing cancer patients during the pandemic, balancing cancer treatment with the risks posed by COVID-19.

Adoptive cell transfer, particularly CAR-T therapies, has shown promise in treating various malignancies, yet challenges remain. A study demonstrated that metabolic engineering to enhance arginine availability improved CAR-T cell proliferation and therapeutic activity in a low arginine microenvironment, which is often detrimental to T cell function (ref: Fultang doi.org/10.1182/blood.2019004500/). Additionally, the development of tandem CARs targeting both CD19 and CD20 in refractory B-cell lymphoma showed improved antitumor activity and stability, suggesting a potential strategy to overcome treatment resistance (ref: Tong doi.org/10.1182/blood.2020005278/). However, the use of oncolytic viruses to enhance CAR-T cell therapy revealed unexpected results, as the inflammatory response led to attrition of CAR-T cells, indicating the complexity of tumor microenvironments (ref: Evgin doi.org/10.1038/s41467-020-17011-z/). Furthermore, protease-activated T-cell bispecific antibodies have been developed to enhance tumor specificity, potentially reducing off-target effects associated with traditional TCBs (ref: Geiger doi.org/10.1038/s41467-020-16838-w/). These studies illustrate the ongoing evolution of CAR-T therapies and the need for innovative strategies to enhance their efficacy and safety.

Tumor biomarkers and genetic alterations play a pivotal role in predicting treatment responses and outcomes. A study on multifocal hepatocellular carcinomas found that smaller tumors exhibited higher immune cell infiltration and better responses to anti-PD-1 therapy, suggesting that tumor size and immune heterogeneity significantly influence treatment efficacy (ref: Huang doi.org/10.1158/1078-0432.CCR-19-3840/). Additionally, research on dual oxidase 1 (DUOX1) revealed its role in limiting the antitumor effects of macrophages, indicating that macrophage activation states can be modulated to enhance therapeutic responses (ref: Meziani doi.org/10.1136/jitc-2020-000622/). Furthermore, oxygen-enhanced optoacoustic tomography demonstrated that targeting heme and oxidative phosphorylation can normalize tumor vascular oxygenation, potentially improving the effectiveness of therapies (ref: Ghosh doi.org/10.1158/0008-5472.CAN-19-3247/). These findings underscore the importance of understanding tumor biology and the immune landscape to identify effective biomarkers and therapeutic targets.

Clinical trials continue to be essential for advancing cancer therapies and understanding their mechanisms. A phase I clinical trial evaluated a novel 5T4 viral vectored vaccination regimen in early-stage prostate cancer, aiming to enhance T-cell immunity against the oncofetal antigen 5T4 (ref: Cappuccini doi.org/10.1136/jitc-2020-000928/). This study highlights the ongoing efforts to develop effective immunotherapies for prostate cancer, which has historically been challenging. Another investigation into lung metastases revealed common immune features across different primary tumor origins, suggesting that immune profiling could guide therapeutic strategies for metastatic disease (ref: García-Mulero doi.org/10.1136/jitc-2019-000491/). Additionally, the role of SOD3 in promoting T cell infiltration into tumors was further explored, indicating its potential as a therapeutic target for enhancing immune responses in cancer (ref: Carmona-Rodríguez doi.org/10.1136/jitc-2019-000432/). These clinical insights emphasize the importance of personalized approaches in cancer treatment, leveraging immune characteristics and novel therapeutic strategies.