Tumor immunotherapy has achieved breakthroughs in the treatment of malignant tumors by activating the host immune system’s antitumor response mechanism. Among various strategies, Toll-like receptor (TLR) agonists have garnered substantial attention due to their unique immunomodulatory capabilities. This work reviews the research progress on the combination of TLR agonists with radiotherapy in tumor immunotherapy, focusing on the clinical translational potential of intratumoral injection strategies. Clinical studies have shown that the in-situ injection of TLR agonists in combination with radiotherapy can effectively suppress primary and metastatic lesions by inducing immunogenic cell death, releasing tumor antigens, activating local immune responses, and triggering abscopal effects. Moreover, novel extended-release formulations and “endogenous vaccine” designs further enhance the safety and durability of treatment. Despite several challenges such as tumor microenvironment suppression and dose optimization, TLR agonists hold promise for the treatment of “cold” tumors lacking innate immunity through combinations with immune checkpoint inhibitors, nanodelivery technologies, and precise biomarker screening.

In situ tumor vaccine has become an important strategy in cancer immunotherapy owing to its ability to induce immune responses locally and overcome tumor heterogeneity. However, the abnormal structure and mechanical properties of the tumor’s physical microenvironment significantly limit the efficiency of vaccine delivery and immune efficacy. In this review, the key factors in the tumor’s physical microenvironment, including solid pressure, interstitial fluid pressure, matrix stiffness, and tissue microstructure, are systematically discussed. Their obstructive roles in immune cell infiltration, antigen presentation, and immune activation are analyzed. The potential of approaches, such as radiotherapy, anti-angiogenic therapy, extracellular matrix degradation agents, nanomaterials, and hydrogel delivery platforms, in reshaping the tumor’s physical microenvironment is explored. This review aims to offer theoretical and practical guidance for optimizing in situ vaccine strategies through the regulation of the tumor’s physical microenvironment, ultimately advancing the precision and effectiveness of cancer immunotherapy.

Chimeric antigen receptor gene-modified T(CAR-T)cell therapy represents an immunotherapeutic approach wherein autologous T cells are genetically engineered ex vivo to express specific chimeric antigen receptors(CARs),expanded,and reinfused into patients to specifically recognize and eliminate tumor cells.Despite substantial efficacy in hematological malignancies,CAR-T cell therapy encounters significant barriers in solid tumors.Immune-related adverse events(irAEs),including cytokine release syndrome(CRS),compromise safety profiles,while tumor-associated antigen(TAA)heterogeneity restricts both single-target CAR-T cell applicability and universal CAR-T cell development.Consequently,breakthrough refinements remain essential for clinical translation in solid tumors.This review examines CAR-T cell therapy for solid tumors,critically evaluating safety and universality enhancement strategies through three core approaches:structural CAR design optimization,universal immune receptor retargeting,and antigen universality augmentation.Each approach undergoes systematic analysis of research pathways,advantages,and limitations,with future trajectories delineated.By synthesizing advances in safety and universal design paradigms,the review aims to establish innovative frameworks for CAR-T cell therapeutic development in solid tumor therapeutics.

Objective:To evaluate the efficacy and safety of radiotherapy as a combined mode with in-situ vaccine for patients with advanced soft tissue sarcoma(STS).Methods:The clinical data of 12 patients with advanced STS who received combination therapy mode at the Cancer Center of Gulou Hospital Affiliated to the School of Medicine of Nanjing University between December 2020 and September 2024 were retrospectively analyzed.All 12 patients received combined therapy.The main radiotherapeutic approach was hypofractionated radiotherapy.The targeted therapy mainly involved Anlotinib(in 10 cases)or Apatinib(in 2 cases).Immunotherapy mainly involved PD-1 antibodies.The primary endpoint was disease control rate(DCR),and the secondary endpoints were objective response rate(ORR)and safety.Results:Among the 12 STS patients who received combined treatment,0 cases achieved CR,4 cases achieved PR;7 cases had SD,and 1 case had PD.The ORR was 33%,and the DCR was 91.7%,among which the DCR of the target lesions was 100%.Among the 12 patients,9 patients experienced grade Ⅰ to grade Ⅱ adverse reactions.The most frequently occurring hematological adverse reactions were anemia(6 cases)and abnormal results of liver function tests(3 cases).The most frequently occurring non-hematological adverse reactions were proteinuria(5 cases),hypertension(4 cases),abnormal thyroid function(3 cases),anorexia(3 cases),and nausea and vomiting(2 cases).Only 2 cases had grade Ⅲ hematological toxicity,and 1 case had grade Ⅲpneumothorax.Conclusion:Radiotherapy as a combined therapy mode with in situ vaccine can achieve a higher DCR in advanced soft tissue sarcomas without serious adverse reactions.This combined treatment modality demonstrates good efficacy and safety.

Ewing sarcoma(EWS)is an invasive and primary bone tumor with a high incidence in children and adolescents.The presence and extent of metastases at the time of diagnosis remains the most important prognostic factor in determining a patient's prognosis.Up now,considerable ambiguity exists regarding the optimal modality for detecting bone marrow metastases.Bone marrow biopsy and/or aspiration(BMBA)is the gold standard for determining bone marrow metastases.This invasive and painful procedure may be amenable to being replaced by 18F-FDG PET/CT because of its high sensitivity in detecting EWS bone and extraosseous metastases.This review provides an overview of the current literature,concludes that there is no longer a systematic consensus on the implementation of BMAB criteria for the diagnosis of bone marrow metastases in EWS,and summarizes the current practical strategies and clinical practices for the diagnosis of EWS bone marrow metastases accordingly.

With the rapid development of tumor immunotherapy in recent years, therapeutic cancer vaccines are attracting increased attention. Compared with personalized neoantigen vaccines, in situ vaccines could form an antigen reservoir in the tumor itself. Subsequently, antitumor immunity is initiated and the response to immune-checkpoint inhibitors of some patients improve without necessitating these patients to undergo the complicated procedures of detecting personalized antigen and customizing and synthesizing antigen peptide. At this stage, the potential of realizing the clinical translation of in situ vaccination is tremendous. In this review, we primarily introduce the mechanisms of radiotherapy and intratumoral immune injection as in situ vaccination and discuss the current status of preclinical study and clinical application of their combination to attract more attention from researchers and clinicians toward in situ vaccination.

Soft tissue sarcoma (STS) is a highly heterogeneous group of malignant tumors originating from mesenchymal tissues. The most common sites of STS are limbs (45%), viscera (21%) and retroperitoneum (17%). The incidence of head and neck soft tissue sarcomas (HNSTS) is the lowest (5%) compared with other areas of the body. Due to numerous functional organs and delicate and complex anatomical structures of the head and neck, it is often difficult to perform radical surgical treatment. Therefore, radiotherapy plays an important role in the treatment of HNSTS. Due to its low incidence, radiotherapy for HNSTS has been rarely studied and captivated little attention. In this article, the present situation and clinical evidence of radiotherapy for HNSTS were summarized, aiming to provide reference for clinical practice.

Immunosuppressive tumor microenvironment is an important obstacle to tumor immunotherapy.Therefore,improving tumor microenvironment to enhance immune response is the key to improve the efficacy of immunotherapy.Based on the basic principle of immunology that the body has a strong response to"foreign"antigens and a weak response to preexisting antigens,pathogen infection can be combined with innate immune-related receptors to enhance the anti-tumor immune response.Pathogen vaccines can induce a"hot"tumor microenvironment with stronger antigen presentation and T lymphocyte activation,showing higher response to immunotherapy and having better security.In this review,we summarized the related studies on pathogen vaccine enhancing tumor immune response,including mixed bacterial vaccine,BCG vaccine,OK-432,synthetic vaccines based on tetanus toxin,modified vaccinia virus,influenza vaccine,Epstein-Barr virus and COVID-19 vaccine.The feasibility,application prospect and challenge of pathogen vaccine in tumor immunotherapy were discussed.

Tumor immunotherapeutics include immune checkpoint inhibitors,adoptive cellular therapy,tumor vaccines,immunomodulators,which regulate or induce anti-tumor activity by blocking immunosuppressive signals,infusing in vitro-induced anti-tumor effector cells,and enhancing the immunogenicity of tumor cells in the fight against cancer.The effect mechanisms of tumor immunotherapy is different from that of other tumor therapeutic approaches,such as surgery and chemotherapy.Therefore,in the evaluation of anti-tumor efficacy,the use of conventional imaging methods to detect the volume change of tumor lesions shows special response patterns such as"false progression"and"superprogression",which cannot timely and accurately evaluate the objective efficacy of tumor immunotherapy.This review is an attempt to focus on those challenges in evaluating immunotherapy efficacy and the latest developments of relevant evaluation criteria,and is aimed at providing reference for the scientific evaluation of tumor immunotherapy efficacy and the selection of appropriate immunotherapy strategies for tumor patients.